1,8-naphthyridinone compounds and uses thereof

ABSTRACT

1,8-naphthyridinone compounds as modulators of an adenosine receptor are provided. The compounds may find use as therapeutic agents for the treatment of diseases mediated through a G-protein-coupled receptor signaling pathway and may find particular use in oncology.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/534,185, filed Jul. 18, 2017, the contents of which are incorporatedby reference in their entirety.

FIELD OF THE INVENTION

This disclosure relates generally to therapeutics for treatment mediatedthrough a G-protein-coupled receptor (GPCR) signaling pathway and, moreparticularly, to compounds that inhibit an adenosine receptor (such asan A_(2A) antagonist). The disclosure also provides pharmaceuticallyacceptable compositions comprising such compounds and methods of usingthe compounds or compositions in the treatment of a disease associatedwith a GPCR signaling pathway.

BACKGROUND OF THE INVENTION

Adenosine receptors (ARs) are distributed throughout the body and areresponsible for numerous biological functions. The seven trans-membraneG-protein-coupled receptors (GPCRs) have been divided into fourdifferent subtypes: A₁, A_(2A), A_(2B), and A₃. The A_(2A) and A_(2B)ARs stimulate activity of the adenylyl cyclase, inducing an increase ofcAMP levels. A_(2A) ARs have a distinct tissue localization, differentbiochemical pathways, and specific pharmacological profiles.

Adenosine is one of the human body's most important neuromodulators inboth the central and the peripheral nervous systems. Adenosine isreleased from tumor cells and its concentration in the extracellularfluid of tumors can reach immunosuppressive levels (Blay et al. (1997),Cancer Res., 57(13), pp. 2602-5). The extracellular fluid of solidcarcinomas contains immunosuppressive concentrations of adenosine. Id.This increase in adenosine concentration is a result of increases inCD73 (ecto-5′-nucleotidase) and CD39 (nucleoside triphosphatedephosphorylase) enzymes, which are responsible for directlycatabolizing ATP into adenosine. These upregulations are triggered byhypoxia and the generation of HIF-1α. High levels of adenosine aroundtumor cells act to regulate multiple immune cells (e.g., CD4⁺ T-cellsand cytotoxic CD8⁺ T-cells) via activation of multiple adenosinereceptor subtypes, but particularly A_(2A) receptors, resulting thesuppressing of pro-inflammatory activities and upregulation ofanti-inflammatory molecules and immunoregulatory cells (Kumar et al.(2013), Adenosine as an endogenous immunoregulator in cancerpathogenesis: where to go? Purinergic Signal., 9(2), pp 145-65 andSitkowsky et al., Hostile, hypoxia-A2-adenosinergic tumor biology as thenext barrier to overcome for tumor immunologists. Cancer Immunol. Res.2(7), pp 598-605; Ohta (2016), A Metabolic Immune Checkpoint: Adenosinein Tumor Microenvironment. Frontiers in Immunology, 7 article#109, pp1-11). It was demonstrated that chimeric antigen receptor (CAR) T cellsupregulate A2ARs upon antigen-specific stimulation in vitro and in vivo(Beavls (2017), Targeting the Adenosine 2A Receptor Enhances ChimericAntigen Receptor T Cell Efficacy. J of Clin Invest. 127 (3): pp929-941).

Survival of cancer cells is dependent on their ability to avoid attackby the immune system. In addition, tumor cells can overtake the immunesystem to facilitate tumor survival and metastasis. Adenosine, whoseconcentration increases within hypoxic regions of solid tumors, has beenrecognized as being able to interfere with the recognition of tumorcells by cytolytic effector cells of the immune system. (Tuite and Riss(2013). Recent developments in the pharmacological treatment ofParkinson's disease. Expert Opin. Investig. Drugs, 12(8) pp 1335-52,Popoli et al. (2002). Blockade of striatal adenosine A_(2A) receptorreduces, through a presynaptic mechanism, quinolinic acid-inducedexcitotoxicity: possible relevance to neuroprotective interventions inneurodegenerative diseases of the striatum, J. Neurosci, 22(5) pp.1967-75, Gessi et al. (2011). Adenosine receptors and cancer. BiochimBiophys Acta, 1808(5), pp. 1400-12).

Although all adenosine receptors now have an increasing number ofrecognized biological roles in tumors, the A_(2A) and A₃ subtypes appearpromising targets for therapeutic development. In particular, activationof A_(2A) receptors leads to immunosuppressive effects, which decreasesanti-tumoral immunity and thereby encourages tumor growth.

The A_(2B) receptor is another potential target for therapeuticdevelopment. Autocrine/paracrine stimulation of A_(2B) expressed ontumor cells is believed to enhance their metastatic potential and A_(2B)blockade may reduce tumor metastasis in an immune-independent manner(Beavis et al. (2013). Blockade of A_(2A) receptors potently suppressesthe metabolism of CD73⁺ Tumors. Proc. Natl. Acad. Sci., 110(36) pp.14711-6). A_(2B) expression also correlates with relapse-free survival(RFS) in triple negative breast cancer suggesting that this pathway maybe clinically relevant. A_(2B) blockade also has the potential tomodulate the immunosuppressive properties of tumor-associated immunecells including dendritic cells and myeloid-derived suppressor cells(MDSCs) (Cekic et al. (2011). Adenosine A2B receptor blockade slowsgrowth of bladder and breast tumors. J. Immunol. 188(1), pp. 198-205;Sorrentino et al. (2015). Myeloid-derived suppressor cells contribute toA_(2B) adenosine receptor-induced VEGF production and angiogenesis in amouse melanoma model. Oncotarget 6(29), pp. 27478-89; Iannone et al.(2013). Blockade of A_(2B) adenosine receptor reduces tumor growth andimmune suppression mediated by myeloid-derived suppressor cells in amouse model of melanoma. Neoplasia, 15(12), pp. 1400-9.

There remains a continuing need for new therapies for the treatment ofdiseases and disorders related to the adenosine signaling pathway.

BRIEF SUMMARY OF THE INVENTION

In one aspect, provided is a compound of the formula (I):

or a tautomer or isomer thereof, or a pharmaceutically acceptable saltof any of the foregoing, wherein A, B, R¹, R², R³, R⁴, and R⁵ are asdetailed herein.

In some embodiments, the compound of the formula (I), or a tautomer orisomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, is of the formula (II) or (III), or a tautomer or isomerthereof, or a pharmaceutically acceptable salt of any of the foregoing,as detailed herein. In some embodiments, the compound of the formula(I), or a tautomer thereof, or a salt of any of the foregoing, is of theformula (II). In some embodiments, the compound of the formula (I), or atautomer thereof, or a salt of any of the foregoing, is of the formula(III).

In another aspect, provided is a method for any one or more of: (a)treating a disease, such as a proliferative disease, in an individual inneed thereof; (b) enhancing an immune response in an individual in needthereof; (c) inhibiting tumor metastasis in an individual in needthereof; (d) modulating the activity of a G protein coupled receptorsignaling pathway in an individual in need thereof; (e) modulating theactivity of an adenosine receptor, such as an A_(2A) receptor, in anindividual in need thereof; and (f) increasing the activity of a naturalkiller cell in an individual in need thereof, wherein the methodcomprises administering to the individual an effective amount of acompound of formula (I), or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing. In someembodiments, provided is a method for any one or more of: (a) treating adisease, such as a proliferative disease, in an individual in needthereof; (b) enhancing an immune response in an individual in needthereof; (c) inhibiting tumor metastasis in an individual in needthereof; (d) modulating the activity of a G protein coupled receptorsignaling pathway in an individual in need thereof; (e) modulating theactivity of an adenosine receptor, such as an A_(2A) receptor, in anindividual in need thereof; and (f) increasing the activity of a naturalkiller cell in an individual in need thereof, wherein the methodcomprises administering to the individual an effective amount of acompound of formula (I), or a tautomer thereof, or a or a salt of any ofthe foregoing. In one aspect, the compound of formula (I) or a tautomerthereof, or a salt of any of the foregoing, is administered to theindividual in combination with another therapeutic agent. In someembodiments, the compound of formula (I) or a tautomer or isomerthereof, or a pharmaceutically acceptable salt of any of the foregoingis administered to the individual in combination with anothertherapeutic agent. In a further aspect of the methods, the compound offormula (I) or a salt thereof is a compound of the formula (II) or (III)or a tautomer thereof, or a or a salt of any of the foregoing. In someembodiments, the compound of formula (I) or a tautomer or isomerthereof, or a pharmaceutically acceptable salt of any of the foregoingis a compound of the formula (II) or (III), or a tautomer or isomerthereof, or a pharmaceutically acceptable salt of any of the foregoing.

Also provided are pharmaceutical compositions comprising (A) a compounddetailed herein, such as a compound of formula (I) or a tautomer orisomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, or a compound of formula (II) or a tautomer or isomerthereof, or a pharmaceutically acceptable salt of any of the foregoing,or a compound of formula (III) or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, and (B) apharmaceutically acceptable carrier or excipient. In some embodiments,provided are pharmaceutical compositions comprising (A) a compounddetailed herein, such as a compound of formula (I) or a tautomerthereof, or a or a salt of any of the foregoing, or a compound offormula (II) or a tautomer thereof, or a or a salt of any of theforegoing, or a compound of formula (III) or a tautomer thereof, or a ora salt of any of the foregoing, and (B) a pharmaceutically acceptablecarrier or excipient. Kits comprising a compound detailed herein or atautomer or isomer thereof, or a pharmaceutically acceptable salt of anyof the foregoing and instructions for use are also provided. Kitscomprising a compound detailed herein or a salt thereof and instructionsfor use are also provided. A compound detailed herein or a tautomer orisomer thereof, or a pharmaceutically acceptable salt of any of theforegoing is also provided for the manufacture of a medicament for thetreatment of cancer. Compounds as detailed herein or a pharmaceuticallyacceptable salt thereof are also provided for the manufacture of amedicament for the treatment of cancer.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For use herein, unless clearly indicated otherwise, use of the terms“a”, “an” and the like refers to one or more.

“Alkenyl” as used herein refers to an unsaturated linear or branchedunivalent hydrocarbon chain or combination thereof, having at least onesite of olefinic unsaturation (i.e., having at least one moiety of theformula C═C) and having the number of carbon atoms designated (i.e.,C₂-C₁₀ means two to ten carbon atoms). The alkenyl group may be in “cis”or “trans” configurations, or alternatively in “E” or “Z”configurations. Particular alkenyl groups are those having 2 to 20carbon atoms (a “C₂-C₂₀ alkenyl”), having 2 to 8 carbon atoms (a “C₂-C₈alkenyl”), having 2 to 6 carbon atoms (a “C₂-C₆ alkenyl”), or having 2to 4 carbon atoms (a “C₂-C₄ alkenyl”). Examples of alkenyl include, butare not limited to, groups such as ethenyl (or vinyl), prop-1-enyl,prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl,but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, homologs andisomers thereof, and the like.

The term “alkyl” refers to and includes saturated linear and branchedunivalent hydrocarbon structures and combination thereof, having thenumber of carbon atoms designated (i.e., C₁-C₁₀ means one to tencarbons). Particular alkyl groups are those having 1 to 20 carbon atoms(a “C₁-C₂₀ alkyl”). More particular alkyl groups are those having 1 to 8carbon atoms (a “C₁-C₈ alkyl”), 3 to 8 carbon atoms (a “C₃-C₈ alkyl”), 1to 6 carbon atoms (a “C₁-C₆ alkyl”), 1 to 5 carbon atoms (a “C₁-C₅alkyl”), or 1 to 4 carbon atoms (a “C₁-C₄ alkyl”). Examples of alkylinclude, but are not limited to, groups such as methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomersof, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

“Alkylene” as used herein refers to the same residues as alkyl, buthaving bivalency. Particular alkylene groups are those having 1 to 6carbon atoms (a “C₁-C₆ alkylene”), 1 to 5 carbon atoms (a “C₁-C₅alkylene”), 1 to 4 carbon atoms (a “C₁-C₄ alkylene”) or 1 to 3 carbonatoms (a “C₁-C₃ alkylene”). Examples of alkylene include, but are notlimited to, groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), and the like.

“Alkynyl” as used herein refers to an unsaturated linear or branchedunivalent hydrocarbon chain or combination thereof, having at least onesite of acetylenic unsaturation (i.e., having at least one moiety of theformula C≡C) and having the number of carbon atoms designated (i.e.,C₂-C₁₀ means two to ten carbon atoms). Particular alkynyl groups arethose having 2 to 20 carbon atoms (a “C₂-C₂₀ alkynyl”), having 2 to 8carbon atoms (a “C₂-C₈ alkynyl”), having 2 to 6 carbon atoms (a “C₂-C₆alkynyl”), or having 2 to 4 carbon atoms (a “C₂-C₄ alkynyl”). Examplesof alkynyl include, but are not limited to, groups such as ethynyl (oracetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl,but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.

The term “aryl” refers to and includes polyunsaturated aromatichydrocarbon groups. Aryl may contain additional fused rings (e.g., from1 to 3 rings), including additionally fused aryl, heteroaryl,cycloalkyl, and/or heterocyclyl rings. In one variation, the aryl groupcontains from 6 to 14 annular carbon atoms. Examples of aryl groupsinclude, but are not limited to, phenyl, naphthyl, biphenyl, and thelike.

The terms “cycloalkyl” or “carbocycle” are used interchangeably andrefer to and include cyclic univalent hydrocarbon structures, which maybe fully saturated, mono- or polyunsaturated, but which arenon-aromatic, having the number of carbon atoms designated (e.g., C₁-C₁₀means one to ten carbons). Cycloalkyl or carbocycle groups can consistof one ring, such as cyclohexyl, or multiple rings, such as adamantyl,but excludes aryl groups. A cycloalkyl or carbocycle comprising morethan one ring may be fused, spiro or bridged, or combinations thereof. Apreferred cycloalkyl or carbocycle is a cyclic hydrocarbon having from 3to 13 annular carbon atoms. A more preferred cycloalkyl or carbocycle isa cyclic hydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈cycloalkyl”). Examples of cycloalkyl or carbocycle groups include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like.

“Halo” or “halogen” refers to elements of the Group 17 series havingatomic number 9 to 85. Preferred halo groups include fluoro, chloro,bromo and iodo. Where a residue is substituted with more than onehalogen, it may be referred to by using a prefix corresponding to thenumber of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl,trihaloaryl etc. refer to aryl and alkyl substituted with two (“di”) orthree (“tri”) halo groups, which may be but are not necessarily the samehalo; thus 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. Analkyl group in which each hydrogen is replaced with a halo group isreferred to as a “perhaloalkyl.” A preferred perhaloalkyl group istrifluoroalkyl (—CF₃). Similarly, “perhaloalkoxy” refers to an alkoxygroup in which a halogen takes the place of each H in the hydrocarbonmaking up the alkyl moiety of the alkoxy group. An example of aperhaloalkoxy group is trifluoromethoxy (—OCF₃).

The term “heteroaryl” refers to and includes unsaturated aromatic cyclicgroups having from 1 to 10 annular carbon atoms and at least one annularheteroatom, including but not limited to heteroatoms such as nitrogen,oxygen and sulfur, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Aheteroaryl group can be attached to the remainder of the molecule at anannular carbon or at an annular heteroatom. Heteroaryl may containadditional fused rings (e.g., from 1 to 3 rings), including additionallyfused aryl, heteroaryl, cycloalkyl, and/or heterocyclyl rings. Examplesof heteroaryl groups include, but are not limited to, pyridyl,pyrimidyl, thiophenyl, furanyl, thiazolyl, and the like. Examples ofheteroaryl groups also include, but are not limited to, pyridyl,pyrimidyl, thiophenyl, furanyl, thiazolyl, oxazolyl, isoxazolyl,thiophenyl, pyrrolyl, pyrazolyl, 1,3,4-oxadiazolyl, imidazolyl,isothiazolyl, triazolyl, 1,3,4-thiadiazolyl, tetrazolyl, benzofuranyl,benzothiophenyl, pyrazolopyridinyl, indazolyl, benzothiazolyl,benzooxazolyl or benzoimidazolyl and the like

In one variation, a heteroaryl containing at least one additional fusedring that is nonaromatic (e.g., cycloakyl or heterocyclyl) is attachedto the parent structure at an annular atom of the additional ring. Inanother variation, a heteroaryl containing at least one additional ringthat is nonaromatic (e.g., cycloakyl or heterocyclyl) is attached to theparent structure at an annular atom of the aromatic ring.

The term “heterocycle” or “heterocyclyl” refers to a saturated or anunsaturated non-aromatic group having from 1 to 10 annular carbon atomsand from 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen,and the like, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Aheterocyclyl group may have a single ring or multiple condensed rings,but excludes heteroaryl groups. A heterocycle comprising more than onering may be fused, spiro or bridged, or any combination thereof. Infused ring systems, one or more of the fused rings can be aryl,cycloalkyl or heterocyclyl. Examples of heterocyclyl groups include, butare not limited to, tetrahydropyranyl, dihydropyranyl, piperidinyl,piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl,2,3-dihydrobenzo[b]thiophen-2-yl, 4-amino-2-oxopyrimidin-1 (2H)-yl, andthe like.

In one variation, a heterocyclyl containing at least one additional ring(such as a fused additional ring) that does not contain a heteroatom isattached to the parent structure at an annular atom of the additionalring. In another variation, a heterocyclyl containing at least oneadditional ring (such as a fused additional ring) that does not containa heteroatom is attached to the parent structure at an annular atom ofthe ring containing a heteroatom.

“Oxo” refers to the moiety ═O.

“Optionally substituted” unless otherwise specified means that a groupmay be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4 or5) of the substituents listed for that group in which the substituentsmay be the same of different. In one embodiment, an optionallysubstituted group has one substituent. In another embodiment, anoptionally substituted group has two substituents. In anotherembodiment, an optionally substituted group has three substituents. Inanother embodiment, an optionally substituted group has foursubstituents. In some embodiments, an optionally substituted group has 1to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3, 1 to 4 or 1 to 5substituents.

A “pharmaceutically acceptable carrier” refers to an ingredient in apharmaceutical formulation, other than an active ingredient, which isnontoxic to a subject. A pharmaceutically acceptable carrier includes,but is not limited to, a buffer, excipient, stabilizer, or preservative.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results including clinical results. For example,beneficial or desired results include, but are not limited to, one ormore of the following: decreasing symptoms resulting from the disease,increasing the quality of life of those suffering from the disease,decreasing the dose of other medications required to treat the disease,delaying the progression of the disease, and/or prolonging survival ofindividuals. In reference to cancers or other unwanted cellproliferation, beneficial or desired results include shrinking a tumor(reducing tumor size); decreasing the growth rate of the tumor (such asto suppress tumor growth); reducing the number of cancer cells;inhibiting, retarding or slowing to some extent and preferably stoppingcancer cell infiltration into peripheral organs; inhibiting (slowing tosome extent and preferably stopping) tumor metastasis; inhibiting tumorgrowth; preventing or delaying occurrence and/or recurrence of tumor;and/or relieving to some extent one or more of the symptoms associatedwith the cancer. In some embodiments, beneficial or desired resultsinclude preventing or delaying occurrence and/or recurrence, such as ofunwanted cell proliferation.

As used herein, “delaying development of a disease” means to defer,hinder, slow, retard, stabilize, and/or postpone development of thedisease (such as cancer). This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease. For example, a late stage cancer, such asdevelopment of metastasis, may be delayed.

As used herein, an “effective dosage” or “effective amount” of compoundor salt thereof or pharmaceutical composition is an amount sufficient toeffect beneficial or desired results. For prophylactic use, beneficialor desired results include results such as eliminating or reducing therisk, lessening the severity of, or delaying the onset of the disease,including biochemical, histological and/or behavioral symptoms of thedisease, its complications and intermediate pathological phenotypespresenting during development of the disease. For therapeutic use,beneficial or desired results include ameliorating, palliating,lessening, delaying or decreasing one or more symptoms resulting fromthe disease, increasing the quality of life of those suffering from thedisease, decreasing the dose of other medications required to treat thedisease, enhancing effect of another medication such as via targeting,delaying the progression of the disease, and/or prolonging survival. Inreference to cancers or other unwanted cell proliferation, an effectiveamount comprises an amount sufficient to cause a tumor to shrink and/orto decrease the growth rate of the tumor (such as to suppress tumorgrowth) or to prevent or delay other unwanted cell proliferation. Insome embodiments, an effective amount is an amount sufficient to delaydevelopment. In some embodiments, an effective amount is an amountsufficient to prevent or delay occurrence and/or recurrence. Aneffective amount can be administered in one or more administrations, inthe case of cancer, the effective amount of the drug or composition may:(i) reduce the number of cancer cells; (ii) reduce tumor size; (iii)inhibit, retard, slow to some extent and preferably stop cancer cellinfiltration into peripheral organs; (iv) inhibit (i.e., slow to someextent and preferably stop) tumor metastasis; (v) inhibit tumor growth;(vi) prevent or delay occurrence and/or recurrence of tumor; and/or(vii) relieve to some extent one or more of the symptoms associated withthe cancer. An effective dosage can be administered in one or moreadministrations. For purposes of this disclosure, an effective dosage ofcompound or a salt thereof, or pharmaceutical composition is an amountsufficient to accomplish prophylactic or therapeutic treatment eitherdirectly or indirectly. It is intended and understood that an effectivedosage of a compound or salt thereof, or pharmaceutical composition mayor may not be achieved in conjunction with another drug, compound, orpharmaceutical composition. Thus, an “effective dosage” may beconsidered in the context of administering one or more therapeuticagents, and a single agent may be considered to be given in an effectiveamount if, in conjunction with one or more other agents, a desirableresult may be or is achieved.

As used herein, the term “individual” is a mammal, including humans. Anindividual includes, but is not limited to, human, bovine, horse,feline, canine, rodent, or primate. In some embodiments, the individualis human. The individual (such as a human) may have advanced disease orlesser extent of disease, such as low tumor burden. In some embodiments,the individual is at an early stage of a proliferative disease (such ascancer). In some embodiments, the individual is at an advanced stage ofa proliferative disease (such as an advanced cancer).

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

It is understood that aspects and variations described herein alsoinclude “consisting” and/or “consisting essentially of” aspects andvariations.

Compounds

In one aspect, provided is a compound of the Formula (I):

or a tautomer or isomer thereof, or a pharmaceutically acceptable saltof any of the foregoing, wherein:

R¹ is H or C₁-C₆ alkyl wherein the C₁-C₆ alkyl of R¹ is optionallysubstituted with oxo or R^(a);

R² and R⁴ are each independently H, R^(b) or oxo;

R³ and R⁵ are each independently H or R^(c);

each R^(a), R^(b), and R^(c) is independently C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, halogen, —CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂,—C═NH(OR⁸), —C(O)R⁸, —OC(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰,—NR⁸C(O)R⁹, —NR⁸C(O)OR⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, —NR⁸S(O)R⁹,—C(O)NR⁸S(O)R⁹, —NR⁸S(O)₂R⁹, —C(O)NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰,—P(O)(OR⁹)(OR¹⁰), C₃-C₆ cycloalkyl, 3-12-membered heterocyclyl, 5- to10-membered heteroaryl, C₆-C₁₄ aryl, —(C₁-C₃ alkylene)CN, —(C₁-C₃alkylene)OR⁸, —(C₁-C₃ alkylene)SR⁸, —(C₁-C₃ alkylene)NR⁹R¹⁰, —(C₁-C₃alkylene)CF₃, —(C₁-C₃ alkylene)NO₂, —C═NH(OR⁸), —(C₁-C₃ alkylene)C(O)R⁸,—(C₁-C₃ alkylene)OC(O)R⁸, —(C₁-C₃ alkylene)C(O)OR⁸, —(C₁-C₃alkylene)C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)OC(O)NR⁹R¹⁰, —(C₁-C₃alkylene)NR⁸C(O)R⁹, —(C₁-C₃ alkylene)NR⁸C(O)OR⁹, —(C₁-C₃alkylene)NR⁸C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)S(O)R⁸, —(C₁-C₃alkylene)S(O)₂R⁸, —(C₁-C₃ alkylene)NR⁸S(O)R⁹, —C(O)(C₁-C₃alkylene)NR⁸S(O)R⁹, —(C₁-C₃ alkylene)NR⁸S(O)₂R⁹, —(C₁-C₃alkylene)C(O)NR⁸S(O)₂R⁹, —(C₁-C₃ alkylene)S(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)₂NR⁹R¹⁰, —(C₁-C₃ alkylene)P(O)(OR⁹)(OR¹⁰), —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-12-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-10-membered heteroaryl) or —(C₁-C₃alkylene)(C₆-C₁₄ aryl), wherein each R^(a), R^(b), and R^(c) isindependently optionally substituted by halogen, oxo, —OR, —NR¹¹R¹²,—C(O)R¹¹, —CN, —S(O)R¹¹, —S(O)₂R¹¹, —P(O)(OR¹¹)(OR¹²), —(C₁-C₃alkylene)OR¹¹, —(C₁-C₃ alkylene)NR¹¹R¹², —(C₁-C₃ alkylene)C(O)R¹¹,—(C₁-C₃ alkylene)S(O)R¹¹, —(C₁-C₃ alkylene)S(O)₂R¹¹, —(C₁-C₃alkylene)P(O)(OR)(OR¹²), C₃-C₈ cycloalkyl, or C₁-C₆ alkyl optionallysubstituted by oxo, —OH or halogen;

-   -   wherein when R¹ is C₁-C₆ alkyl, R⁴ is other than —NR⁹R¹⁰ and R³        is other than —C(O)R⁸;

------ is a single bond or a double bond, wherein when ------ is adouble bond, R² is oxo;

is a single bond or a double bond, wherein when

is a double bond, R⁴ is oxo;

-   -   one of ------ and        is a double bond and the other is a single bond;

A is C₆-C₁₂ aryl, 5- to 10-membered heteroaryl, 9- to 10-memberedcarbocycle, or 9- to 10-membered heterocycle, wherein the C₆-C₁₂ aryl,5- to 10-membered heteroaryl, 9- to 10-membered carbocycle, or 9- to10-membered heterocycle of A is optionally further substituted with R⁶;

B is phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered carbocycle,5- to 6-membered heterocycle, or 9- to 10-membered heteroaryl, whereinthe phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered carbocycle, 5-to 6-membered heterocycle, or 9- to 10-membered heteroaryl of B isoptionally further substituted with R⁷;

wherein when B is 5- to 6-membered heterocycle, A is other than phenylor pyridyl optionally further substituted with R⁷;

each R⁶ and R⁷ is independently oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, halogen, —CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C═NH(OR⁸), —C(O)R⁸,—OC(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)OR⁹,—NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, —NR⁸S(O)R⁹, —C(O)NR⁸S(O)R⁹,—NR⁸S(O)₂R⁹, —C(O)NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰,—P(O)(OR⁹)(OR¹⁰), C₃-C₆ cycloalkyl, 3-12-membered heterocyclyl, 5- to10-membered heteroaryl, C₆-C₁₄ aryl, —(C₁-C₃ alkylene)CN, —(C₁-C₃alkylene)OR⁸, —(C₁-C₃ alkylene)SR⁸, —(C₁-C₃ alkylene)NR⁹R¹⁰, —(C₁-C₃alkylene)CF₃, —(C₁-C₃ alkylene)NO₂, —C═NH(OR⁸), —(C₁-C₃ alkylene)C(O)R⁸,—(C₁-C₃ alkylene)OC(O)R⁸, —(C₁-C₃ alkylene)C(O)OR⁸, —(C₁-C₃alkylene)C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)OC(O)NR⁹R¹⁰, —(C₁-C₃alkylene)NR⁸C(O)R⁹, —(C₁-C₃ alkylene)NR⁸C(O)OR⁹, —(C₁-C₃alkylene)NR⁸C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)S(O)R⁸, —(C₁-C₃alkylene)S(O)₂R⁸, —(C₁-C₃ alkylene)NR⁸S(O)R⁹, —C(O)(C₁-C₃alkylene)NR⁸S(O)R⁹, —(C₁-C₃ alkylene)NR⁸S(O)₂R⁹, —(C₁-C₃alkylene)C(O)NR⁸S(O)₂R⁹, —(C₁-C₃ alkylene)S(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)₂NR⁹R¹⁰, —(C₁-C₃ alkylene)P(O)(OR⁹)(OR¹⁰), —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-12-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-10-membered heteroaryl) or —(C₁-C₃alkylene)(C₆-C₁₄ aryl), wherein each R⁶ and R⁷ is independentlyoptionally substituted by halogen, oxo, —OR¹¹, —NR¹¹R¹², —C(O)R¹¹, —CN,—S(O)R¹¹, —S(O)₂R¹¹, —P(O)(OR¹¹)(OR¹²), —(C₁-C₃ alkylene)OR¹¹, —(C₁-C₃alkylene)NR¹¹R¹², —(C₁-C₃ alkylene)C(O)R¹¹, —(C₁-C₃ alkylene)S(O)R¹¹,—(C₁-C₃ alkylene)S(O)₂R¹¹, —(C₁-C₃ alkylene)P(O)(OR¹¹)(OR¹²), C₃-C₈cycloalkyl, or C₁-C₆ alkyl optionally substituted by oxo, —OH orhalogen;

each R⁸ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5-6-membered heteroaryl,3-6-membered heterocyclyl, —(C₁-C₃ alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃alkylene)(C₆-C₁₄ aryl), —(C₁-C₃ alkylene)(5-6-membered heteroaryl), or—(C₁-C₃ alkylene)(3-6-membered heterocyclyl), wherein the C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl,5-6-membered heteroaryl, 3-6-membered heterocyclyl, —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(C₆-C₁₄ aryl), —(C₁-C₃alkylene)(5-6-membered heteroaryl), and —(C₁-C₃ alkylene)(3-6-memberedheterocyclyl) of R⁸ are independently optionally substituted by halogen,oxo, —CN, —OR¹³, —NR¹³R¹⁴, —P(O)(OR¹³)(OR¹⁴), phenyl optionallysubstituted by halogen, or C₁-C₆ alkyl optionally substituted byhalogen, —OH or oxo;

R⁹ and R¹⁰ are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5-6-membered heteroaryl,3-6 membered heterocyclyl, —(C₁-C₃ alkylene)NR¹¹R¹², —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-6-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-6-membered heteroaryl) or —(C₁-C₃alkylene)(C₆ aryl), wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5-6-membered heteroaryl, 3-6membered heterocyclyl, —(C₁-C₃ alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃alkylene)(3-6-membered heterocyclyl), —(C₁-C₃ alkylene)(5-6-memberedheteroaryl) and —(C₁-C₃ alkylene)(C₆ aryl) of R⁹ and R¹⁰ areindependently optionally substituted by halogen, oxo, —CN, —OR¹³,—NR¹³R¹⁴ or C₁-C₆ alkyl optionally substituted by halogen, —OH or oxo;

-   -   or R⁹ and R¹⁰ are taken together with the atom to which they        attached to form a 3-6 membered heterocyclyl optionally        substituted by halogen, oxo, —OR¹³, —NR¹³R¹⁴ or C₁-C₆ alkyl        optionally substituted by halogen, oxo or —OH;

R¹¹ and R¹² are each independently hydrogen, C₁-C₆ alkyl optionallysubstituted by halogen or oxo, C₂-C₆ alkenyl optionally substituted byhalogen or oxo, or C₂-C₆ alkynyl optionally substituted by halogen oroxo; or R¹¹ and R¹² are taken together with the atom to which theyattached to form a 3-6 membered heterocyclyl optionally substituted byhalogen, oxo or C₁-C₆ alkyl optionally substituted by halogen or oxo;and

R¹³ and R¹⁴ are each independently hydrogen, C₁-C₆ alkyl optionallysubstituted by halogen or oxo, C₂-C₆ alkenyl optionally substituted byhalogen or oxo, or C₂-C₆ alkynyl optionally substituted by halogen oroxo;

-   -   or R¹³ and R¹⁴ are taken together with the atom to which they        attached to form a 3-6 membered heterocyclyl optionally        substituted by halogen, oxo or C₁-C₆ alkyl optionally        substituted by oxo or halogen.

In some embodiments of a compound of the Formula (I):

or a tautomer thereof, or a salt of any of the foregoing, wherein:

R¹ is H or C₁-C₆ alkyl wherein the C₁-C₆ alkyl of R¹ is optionallysubstituted with oxo or R^(a);

R² and R⁴ are each independently H, R^(b) or oxo;

R³ and R⁵ are each independently H or R^(c);

each R^(a), R^(b), and R^(c) is independently C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, halogen, —CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂,—C═NH(OR⁸), —C(O)R⁸, —OC(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰,—NR⁸C(O)R⁹, —NR⁸C(O)OR⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, —NR⁸S(O)R⁹,—C(O)NR⁸S(O)R⁹, —NR⁸S(O)₂R⁹, —C(O)NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰,—P(O)(OR⁹)(OR¹⁰), C₃-C₆ cycloalkyl, 3-12-membered heterocyclyl, 5- to10-membered heteroaryl, C₆-C₁₄ aryl, —(C₁-C₃ alkylene)CN, —(C₁-C₃alkylene)OR⁸, —(C₁-C₃ alkylene)SR⁸, —(C₁-C₃ alkylene)NR⁹R¹⁰, —(C₁-C₃alkylene)CF₃, —(C₁-C₃ alkylene)NO₂, —C═NH(OR⁸), —(C₁-C₃ alkylene)C(O)R⁸,—(C₁-C₃ alkylene)OC(O)R⁸, —(C₁-C₃ alkylene)C(O)OR⁸, —(C₁-C₃alkylene)C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)OC(O)NR⁹R¹⁰, —(C₁-C₃alkylene)NR⁸C(O)R⁹, —(C₁-C₃ alkylene)NR⁸C(O)OR⁹, —(C₁-C₃alkylene)NR⁸C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)S(O)R⁸, —(C₁-C₃alkylene)S(O)₂R⁸, —(C₁-C₃ alkylene)NR⁸S(O)R⁹, —C(O)(C₁-C₃alkylene)NR⁸S(O)R⁹, —(C₁-C₃ alkylene)NR⁸S(O)₂R⁹, —(C₁-C₃alkylene)C(O)NR⁸S(O)₂R⁹, —(C₁-C₃ alkylene)S(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)₂NR⁹R¹⁰, —(C₁-C₃ alkylene)P(O)(OR⁹)(OR¹⁰), —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-12-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-10-membered heteroaryl) or —(C₁-C₃alkylene)(C₆-C₁₄ aryl), wherein each R^(a), R^(b), and R^(c) isindependently optionally substituted by halogen, oxo, —OR, —NR¹¹R¹²,—C(O)R¹¹, —CN, —S(O)R¹¹, —S(O)₂R¹¹, —P(O)(OR¹¹)(OR¹²), —(C₁-C₃alkylene)OR¹¹, —(C₁-C₃ alkylene)NR¹¹R¹², —(C₁-C₃ alkylene)C(O)R¹¹,—(C₁-C₃ alkylene)S(O)R¹¹, —(C₁-C₃ alkylene)S(O)₂R¹¹, —(C₁-C₃alkylene)P(O)(OR¹¹)(OR¹²), C₃-C₈ cycloalkyl, or C₁-C₆ alkyl optionallysubstituted by oxo, —OH or halogen;

-   -   wherein when R¹ is C₁-C₆ alkyl, R⁴ is other than —NR⁹R¹⁰ and R³        is other than —OC(O)R⁸;

------ is a single bond or a double bond, wherein when ------ is adouble bond, R² is OXO;

is a single bond or a double bond, wherein when

is a double bond, R⁴ is oxo;

-   -   one of ------ and        is a double bond and the other is a single bond;

A is C₆-C₁₂ aryl, 5- to 10-membered heteroaryl, 9- to 10-memberedcarbocycle, or 9- to 10-membered heterocycle, wherein the C₆-C₁₂ aryl,5- to 10-membered heteroaryl, 9- to 10-membered carbocycle, or 9- to10-membered heterocycle of A is optionally further substituted with R⁶;

B is phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered carbocycle,5- to 6-membered heterocycle, or 9- to 10-membered heteroaryl, whereinthe phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered carbocycle, 5-to 6-membered heterocycle, or 9- to 10-membered heteroaryl of B isoptionally further substituted with R⁷;

wherein when B is 5- to 6-membered heterocycle, A is other than phenylor pyridyl optionally further substituted with R⁷;

each R⁶ and R⁷ is independently oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, halogen, —CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C═NH(OR⁸), —C(O)R⁸,—OC(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)OR⁹,—NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, —NR⁸S(O)R⁹, —C(O)NR⁸S(O)R⁹,—NR⁸S(O)₂R⁹, —C(O)NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰,—P(O)(OR⁹)(OR¹⁰), C₃-C₆ cycloalkyl, 3-12-membered heterocyclyl, 5- to10-membered heteroaryl, C₆-C₁₄ aryl, —(C₁-C₃ alkylene)CN, —(C₁-C₃alkylene)OR⁸, —(C₁-C₃ alkylene)SR⁸, —(C₁-C₃ alkylene)NR⁹R¹⁰, —(C₁-C₃alkylene)CF₃, —(C₁-C₃ alkylene)NO₂, —C═NH(OR⁸), —(C₁-C₃ alkylene)C(O)R⁸,—(C₁-C₃ alkylene)OC(O)R⁸, —(C₁-C₃ alkylene)C(O)OR⁸, —(C₁-C₃alkylene)C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)OC(O)NR⁹R¹⁰, —(C₁-C₃alkylene)NR⁸C(O)R⁹, —(C₁-C₃ alkylene)NR⁸C(O)OR⁹, —(C₁-C₃alkylene)NR⁸C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)S(O)R⁸, —(C₁-C₃alkylene)S(O)₂R⁸, —(C₁-C₃ alkylene)NR⁸S(O)R⁹, —C(O)(C₁-C₃alkylene)NR⁸S(O)R⁹, —(C₁-C₃ alkylene)NR⁸S(O)₂R⁹, —(C₁-C₃alkylene)C(O)NR⁸S(O)₂R⁹, —(C₁-C₃ alkylene)S(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)₂NR⁹R¹⁰, —(C₁-C₃ alkylene)P(O)(OR⁹)(OR¹⁰), —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-12-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-10-membered heteroaryl) or —(C₁-C₃alkylene)(C₆-C₁₄ aryl), wherein each R⁶ and R⁷ is independentlyoptionally substituted by halogen, oxo, —OR¹¹, —NR¹¹R¹², —C(O)R¹¹, —CN,—S(O)R¹¹, —S(O)₂R¹¹, —P(O)(OR¹¹)(OR¹²), —(C₁-C₃ alkylene)OR¹¹, —(C₁-C₃alkylene)NR¹¹R¹², —(C₁-C₃ alkylene)C(O)R¹¹, —(C₁-C₃ alkylene)S(O)R¹¹,—(C₁-C₃ alkylene)S(O)₂R¹¹, —(C₁-C₃ alkylene)P(O)(OR¹¹)(OR¹²), C₃-C₈cycloalkyl, or C₁-C₆ alkyl optionally substituted by oxo, —OH orhalogen;

R⁸ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5-6-membered heteroaryl or 3-6-memberedheterocyclyl, wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5-6-membered heteroaryl and 3-6-memberedheterocyclyl are independently optionally substituted by halogen, oxo,—CN, —OR¹³, —NR¹³R¹⁴, —P(O)(OR¹³)(OR¹⁴), phenyl optionally substitutedby halogen, or C₁-C₆ alkyl optionally substituted by halogen, —OH oroxo;

R⁹ and R¹⁰ are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5-6-membered heteroaryl or3-6 membered heterocyclyl, wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5-6-membered heteroaryl and 3-6membered heterocyclyl are independently optionally substituted byhalogen, oxo, —CN, —OR¹³, —NR¹³R¹⁴ or C₁-C₆ alkyl optionally substitutedby halogen, —OH or oxo;

-   -   or R⁹ and R¹⁰ are taken together with the atom to which they        attached to form a 3-6 membered heterocyclyl optionally        substituted by halogen, oxo, —OR¹³, —NR¹³R¹⁴ or C₁-C₆ alkyl        optionally substituted by halogen, oxo or —OH;

R¹¹ and R¹² are each independently hydrogen, C₁-C₆ alkyl optionallysubstituted by halogen or oxo, C₂-C₆ alkenyl optionally substituted byhalogen or oxo, or C₂-C₆ alkynyl optionally substituted by halogen oroxo;

-   -   or R¹¹ and R¹² are taken together with the atom to which they        attached to form a 3-6 membered heterocyclyl optionally        substituted by halogen, oxo or C₁-C₆ alkyl optionally        substituted by halogen or oxo; and

R¹³ and R¹⁴ are each independently hydrogen, C₁-C₆ alkyl optionallysubstituted by halogen or oxo, C₂-C₆ alkenyl optionally substituted byhalogen or oxo, or C₂-C₆ alkynyl optionally substituted by halogen oroxo;

-   -   or R¹³ and R¹⁴ are taken together with the atom to which they        attached to form a 3-6 membered heterocyclyl optionally        substituted by halogen, oxo or C₁-C₆ alkyl optionally        substituted by oxo or halogen.

In some embodiments of the compound of Formula (I), A is selected fromthe group consisting of C₆-C₁₂ aryl and 5- to 10-membered heteroaryl,wherein the C₆-C₁₂ aryl and 5- to 10-membered heteroaryl of A isoptionally further substituted with R⁶. In some embodiments of thecompound of Formula (I), B is selected from the group consisting ofphenyl and 5- to 6-membered heteroaryl, wherein the phenyl and 5- to6-membered heteroaryl of B is optionally further substituted with R⁷. Insome embodiments of the compound of Formula (I), A is selected from thegroup consisting of C₆-C₁₂ aryl and 5- to 10-membered heteroaryl,wherein the C₆-C₁₂ aryl and 5- to 10-membered heteroaryl of A isoptionally further substituted with R⁶ and B is selected from the groupconsisting of phenyl and 5- to 6-membered heteroaryl, wherein the phenyland 5- to 6-membered heteroaryl of B is optionally further substitutedwith R⁷.

In some embodiments of Formula (I), R^(a), R^(b), and R^(c) areindependently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —CN,—OR⁸, —SR⁸, —NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸,—S(O)₂R, —NR⁸S(O)R⁹, —NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰, C₃-C₆cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl orC₆-C₁₄ aryl.

In some embodiments of Formula (I), R^(a), R^(b), and R^(c) areindependently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —CN,—OR⁸, —SR⁸, —NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, C₃-C₆ cycloalkyl,3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C₆-C₁₄ aryl.

In some embodiments of Formula (I), R^(a), R^(b), and R^(c) areindependently C₁-C₆ alkyl, halogen, —CN, —OR⁸, —SR⁸ or —NR⁹R¹⁰,

In some embodiments of Formula (I), R^(a), R^(b), and R^(c) areindependently —CH₃, halogen, —CN or —OCH₃.

In some embodiments of the compound of Formula (I), R¹ is H or methyl.

In some embodiments of the compound of Formula (I), R⁵ is H, C₁-C₆alkyl, halogen, —CN, or —OR⁸.

In some embodiments of the compound of Formula (I), R¹, R², R³, and R⁵are each H and R⁴ is oxo. In some embodiments of the compound of Formula(I), R¹, R³, R⁴, and R⁵ are each H and R² is oxo.

In some embodiments, provided is a compound of Formula (II):

or a tautomer or isomer thereof, or a pharmaceutically acceptable saltof any of the foregoing, wherein A, B, R¹, R³, R⁴, and R⁵ are as definedfor Formula (I).

In some embodiments of a compound of Formula (II), at least one of R³,R⁴, and R⁵ is not H. In some embodiments, at least one of R³, R⁴, and R⁵is C₁-C₆ alkyl, halogen, C₆-C₁₄ aryl, —CN, or —OR⁸. In some embodiments,R¹, R³, R⁴, and R⁵ are each H.

In some embodiments, provided is a compound of Formula (III):

or a tautomer or isomer thereof, or a pharmaceutically acceptable saltof any of the foregoing, wherein A, B, R¹, R², R³, and R⁵ are as definedfor Formula (I).

In some embodiments of a compound of Formula (III), at least one of R²,R³, and R⁵ is not H. In some embodiments, at least one of R², R³, and R⁵is C₁-C₆ alkyl, halogen, C₆-C₁₄ aryl, —CN, or —OR⁸. In some embodiments,R¹, R², R³, and R⁵ are each H.

In some embodiments of a compound of Formula (I), (II), or (III), R¹ isC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —CN, —OR⁸, —SR⁸,—NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸,—NR⁸S(O)R⁹, —NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰, C₃-C₆ cycloalkyl,3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C₆-C₁₄ aryl.In some embodiments of a compound of Formula (I), (II), or (III), R¹ isC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —CN, —OR⁸, —SR⁸,—NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, C₃-C₆ cycloalkyl, 3-12-memberedheterocyclyl, 5- to 10-membered heteroaryl or C₆-C₁₄ aryl. In someembodiments of a compound of Formula (I), (II), or (III), R¹ is C₁-C₆alkyl, halogen, —CN, —OR, —SR⁸ or —NR⁹R¹⁰. In some embodiments of acompound of Formula (I), (II), or (III), R¹ is —CH₃, halogen, —CN or—OCH₃. In some embodiments of a compound of Formula (I), (II), or (III),R¹ is H or methyl. In some embodiments of a compound of Formula (I),(II), or (III), R¹ is H, C₁-C₆ alkyl, halogen, —CN, or —OR⁸. In someembodiments of a compound of Formula (I), (II), or (III), R¹ is H orC₁-C₆ alkyl. In some embodiments of a compound of Formula (I), (II), or(III), R¹ is H or methyl. In some embodiments, R¹ is H.

In some embodiments of a compound of Formula (I), (II), or (III), R² isC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —CN, —OR, —SR⁸,—NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸,—NR⁸S(O)R⁹, —NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰, C₃-C₆ cycloalkyl,3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C₆-C₁₄ aryl.In some embodiments of a compound of Formula (I), (II), or (III), R² isC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —CN, —OR⁸, —SR⁸,—NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, C₃-C₆ cycloalkyl, 3-12-memberedheterocyclyl, 5- to 10-membered heteroaryl or C₆-C₁₄ aryl. In someembodiments of a compound of Formula (I), (II), or (III), R² is C₁-C₆alkyl, halogen, —CN, —OR⁸, —SR⁸ or —NR⁹R¹⁰. In some embodiments of acompound of Formula (I), (II), or (III), R² is —CH₃, halogen, —CN or—OCH₃. In some embodiments of a compound of Formula (I), (II), or (III),R² is H or methyl. In some embodiments of a compound of Formula (I),(II), or (III), R² is H, C₁-C₆ alkyl, halogen, —CN, or —OR⁸. In someembodiments of a compound of Formula (I), (II), or (III), R² is oxo.

In some embodiments of a compound of Formula (I), (II), or (III), R³ isC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —CN, —OR, —SR⁸,—NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸,—NR⁸S(O)R⁹, —NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰, C₃-C₆ cycloalkyl,3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C₆-C₁₄ aryl.In some embodiments of a compound of Formula (I), (II), or (III), R³ isC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —CN, —OR⁸, —SR⁸,—NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, C₃-C₆ cycloalkyl, 3-12-memberedheterocyclyl, 5- to 10-membered heteroaryl or C₆-C₁₄ aryl. In someembodiments of a compound of Formula (I), (II), or (III), R³ is C₁-C₆alkyl, halogen, —CN, —OR⁸, —SR⁸ or —NR⁹R¹⁰. In some embodiments of acompound of Formula (I), (II), or (III), R³ is —CH₃, halogen, —CN or—OCH₃. In some embodiments of a compound of Formula (I), (II), or (III),R³ is H or methyl. In some embodiments of a compound of Formula (I),(II), or (III), R³ is H, C₁-C₆ alkyl, halogen, —CN, or —OR⁸.

In some embodiments of a compound of Formula (I), (II), or (III), R⁴ isC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —CN, —OR, —SR⁸,—NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R,—NR⁸S(O)R⁹, —NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰, C₃-C₆ cycloalkyl,3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C₆-C₁₄ aryl.In some embodiments of a compound of Formula (I), (II), or (III), R⁴ isC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —CN, —OR⁸, —SR⁸,—NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, C₃-C₆ cycloalkyl, 3-12-memberedheterocyclyl, 5- to 10-membered heteroaryl or C₆-C₁₄ aryl. In someembodiments of a compound of Formula (I), (II), or (III), R⁴ is C₁-C₆alkyl, halogen, —CN, —OR⁸, —SR⁸ or —NR⁹R¹⁰. In some embodiments of acompound of Formula (I), (II), or (III), R⁴ is —CH₃, halogen, —CN or—OCH₃. In some embodiments of a compound of Formula (I), (II), or (III),R⁴ is H or methyl. In some embodiments of a compound of Formula (I),(II), or (III), R⁴ is H, C₁-C₆ alkyl, halogen, —CN, or —OR⁸. In someembodiments of a compound of Formula (I), (II), or (III), R⁴ is oxo.

In some embodiments of a compound of Formula (I), (II), or (III), R⁵ isC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —CN, —OR⁸, —SR⁸,—NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸,—NR⁸S(O)R⁹, —NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰, C₃-C₆ cycloalkyl,3-12-membered heterocyclyl, 5- to 10-membered heteroaryl or C₆-C₁₄ aryl.In some embodiments of a compound of Formula (I), (II), or (III), R⁵ isC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen, —CN, —OR⁸, —SR⁸,—NR⁹R¹⁰, —C(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, C₃-C₆ cycloalkyl, 3-12-memberedheterocyclyl, 5- to 10-membered heteroaryl or C₆-C₁₄ aryl. In someembodiments of a compound of Formula (I), (II), or (III), R⁵ is C₁-C₆alkyl, halogen, —CN, —OR⁸, —SR⁸ or —NR⁹R¹⁰. In some embodiments of acompound of Formula (I), (II), or (III), R⁵ is —CH₃, halogen, —CN or—OCH₃. In some embodiments of a compound of Formula (I), (II), or (III),R⁵ is H or methyl. In some embodiments of a compound of Formula (I),(II), or (III), R⁵ is H, C₁-C₆ alkyl, halogen, —CN, or —OR⁸. In someembodiments of a compound of Formula (I), (II), or (III), R⁵ is H, C₁-C₆alkyl, halogen, —CN, or —OR⁸. In some embodiments, R⁵ is H. Inparticular embodiments of a compound of Formula (I), (II), or (III), R¹is H or C₁-C₆ alkyl (such as methyl) and R⁵ is H, C₁-C₆ alkyl, halogen,—CN, or —OR⁸.

In some embodiments of a compound of Formula (I), (II), or (III), A isC₆-C₁₂ aryl optionally further substituted with R⁶. In some embodiments,A is phenyl or naphthyl, optionally substituted with R⁶. In someembodiments, A is phenyl. In some embodiments, A is naphthyl. In someembodiments, A is phenyl or naphthyl, substituted with one or moregroups selected from halogen, —CN, —OR, —SR⁸, —NR⁹R¹⁰, —NO₂, —C(O)R⁸,—C(O)OR⁸, —C(O)NR⁹R¹⁰, —C(O)NR⁸S(O)₂R⁹, —OC(O)R⁸, —OC(O)NR⁹R¹⁰,—NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, C₃-C₆ cycloalkyl andC₁-C₆ alkyl optionally substituted by halogen. In some embodiments, A isphenyl, substituted with one or more groups selected from halogen, —CN,—OH, —OC₁-C₆ alkyl, —NH₂, —NO₂, C₃-C₆ cycloalkyl and C₁-C₆ alkyloptionally substituted by halogen. In some embodiments, A is phenyl,substituted with one or more groups selected from halogen, —OH, andC₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), (II), or (III), A is5- to 10-membered heteroaryl optionally further substituted with R⁶. Insome embodiments, A is selected from the group consisting of pyridyl,quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl,naphthyridinyl, benzoxazolyl, benzothiazolyl, benzoimidazoyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl,oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl,thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzofuranyl, benzoisoxazolyl, benzoxadiazolyl, benzothiophenyl,benzoisothiazolyl, benzothiadiazolyl, pyrrolopyridinyl,pyrazolopyridinyl, imidazopyridinyl, triazolopyridinyl, furopyridinyl,oxazolopyridinyl, isoxazolopyridinyl, oxadiazolopyridinyl,thienopyridinyl, thiazolopyridinyl, isothiazolopyridinyl,thiadiazolopyridinyl, thienopyridinyl, phthalazinyl, pyrazolothiazolyl,pyrazolothiazolyl and imidazothiazolyl, each optionally substituted withR⁶. In one variation, the optional substitution with R⁶ provides amoiety that is unsubstituted. In one variation, the optionalsubstitution with R⁶ provides a moiety that is substituted with 1-3 R⁶,which may be the same or different.

In some embodiments, A is a 10-membered heteroaryl optionally furthersubstituted with R⁶, wherein the 10-membered heteroaryl is a 6/6-ringfused system (i.e., a ring system formed by fusing a 6-membered ringwith a 6-membered ring). In some embodiments, A is a 9-memberedheteroaryl, wherein the 9-membered heteroaryl is a 6/5-ring fused system(i.e., a ring system formed by fusing a 6-membered ring with a5-membered ring). In some embodiments, the 6/5-ring fused system of A isattached to the rest of the compound via the 6-membered ring. In otherembodiments, the 6/5-ring fused system of A is attached to the rest ofthe compound via the 5-membered ring.

In some embodiments, A is selected from the group consisting of:

each optionally substituted with R⁶ and where the wavy line denotesattachment to the parent structure. In one variation, such groups arenot further substituted with R⁶. In some embodiments, A is selected fromthe group consisting of:

each optionally substituted with R⁶. In one variation, such groups arenot further substituted with R⁶. In one variation, such groups arefurther substituted with 1-3 R⁶, which may be the same or different. Insome of these embodiments, A is 5- to 10-membered heteroaryl optionallyfurther substituted with one or more groups selected from halogen, —CN,—OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰,—C(O)NR⁸S(O)₂R⁹, —OC(O)R⁸, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰,—S(O)R⁸, —S(O)₂R⁸, C₃-C₆ cycloalkyl and C₁-C₆ alkyl optionallysubstituted by halogen. In some embodiments, A is 5- to 10-memberedheteroaryl optionally further substituted with one or more groupsselected from C₁-C₆ alkyl, halogen, —CN, —OH, and —OC₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), (II), or (III), A is a9- to 10-membered carbocycle optionally further substituted with R⁶. Insome embodiments, A is a 10-membered carbocycle, wherein the 10-memberedcarbocycle is a 6/6-ring fused system (i.e., a ring system formed byfusing a 6-membered ring with a 6-membered ring). In some embodiments, Ais a 9-membered carbocycle, wherein the 9-membered carbocycle is a6/5-ring fused system (i.e., a ring system formed by fusing a 6-memberedring with a 5-membered ring). In some embodiments, the 6/5-ring fusedsystem of A is attached to the rest of the compound via the 6-memberedring. In other embodiments, the 6/5-ring fused system of A is attachedto the rest of the compound via the 5-membered ring. In someembodiments, A is a fully saturated 9- to 10-membered carbocycle. Insome embodiments, A is a partially saturated 9- to 10-memberedcarbocycle. In some embodiments of a compound of Formula (I), (II), or(III), A is selected from the group consisting of decahydronaphthalenyl,octahydroindenyl, 1,2,3,4-tetrahydronaphthalenyl, and2,3-dihydroindenyl, each optionally substituted with R⁶. In someembodiments, A is a 9- to 10-membered carbocycle optionally furthersubstituted with one or more groups selected from halogen, —CN, —OR⁸,—SR⁸, —NR⁹R¹⁰, —NO₂, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰, —C(O)NR⁸S(O)₂R⁹,—OC(O)R⁸, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸,C₃-C₆ cycloalkyl and C₁-C₆ alkyl optionally substituted by halogen. Insome embodiments, A is a 9- to 10-membered carbocycle optionally furthersubstituted with one or more groups selected from C₁-C₆ alkyl, halogen,—CN, —OH, and —OC₁-C₆ alkyl.

In some embodiments, A is a 9- to 10-membered heterocycle optionallyfurther substituted with R⁶. In some embodiments, A is a 10-memberedheterocycle optionally further substituted with R⁶, wherein the10-membered heterocycle is a 6/6-ring fused system (i.e., a ring systemformed by fusing a 6-membered ring with a 6-membered ring). In someembodiments, A is a 9-membered heterocycle, wherein the 9-memberedheterocycle is a 6/5-ring fused system (i.e., a ring system formed byfusing a 6-membered ring with a 5-membered ring). In some embodiments,the 6/5-ring fused system of A is attached to the rest of the compoundvia the 6-membered ring. In other embodiments, the 6/5-ring fused systemof A is attached to the rest of the compound via the 5-membered ring. Insome embodiments, A is a fully saturated 9- to 10-membered heterocycle.In some embodiments, A is a partially saturated 9- to 10-memberedheterocycle. In some embodiments, A is selected from the groupconsisting of tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, indolinyl, isoindolinyl,tetrahydronaphthyridinyl and hexahydrobenzoimidazolyl, each optionallyfurther substituted with R⁶. In some embodiments, A is a 9- to10-membered heterocycle optionally further substituted with one or moregroups selected from halogen, —CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C(O)R⁸,—C(O)OR⁸, —C(O)NR⁹R¹⁰, —C(O)NR⁸S(O)₂R⁹, —OC(O)R⁸, —OC(O)NR⁹R¹⁰,—NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, C₃-C₆ cycloalkyl andC₁-C₆ alkyl optionally substituted by halogen. In some embodiments, A isa 9- to 10-membered heterocycle optionally further substituted with oneor more groups selected from C₁-C₆ alkyl, halogen, —CN, —OH, and —OC₁-C₆alkyl. In some embodiments, A is selected from the group consisting of

each optionally substituted with R⁶. In some embodiments, such groupsare not further substituted with R⁶. In some embodiments, such groupsare further substituted with 1-3 R⁶, which may be the same or different.In some of these embodiments R⁶ is independently selected from the groupconsisting of halogen, —CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C(O)R⁸,—C(O)OR⁸, —C(O)NR⁹R¹⁰, —C(O)NR⁸S(O)₂R⁹, —OC(O)R⁸, —OC(O)NR⁹R¹⁰,—NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, C₃-C₆ cycloalkyl andC₁-C₆ alkyl optionally substituted by halogen. In some embodiments, R⁶is independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, —OH, and —OC₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), (II), or (III), eachR⁶ is independently selected from the group consisting of halogen, —CN,—OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰,—C(O)NR⁸S(O)₂R⁹, —OC(O)R⁸, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰,—S(O)R⁸, —S(O)₂R⁸, C₃-C₆ cycloalkyl and C₁-C₆ alkyl optionallysubstituted by halogen. In some embodiments, R⁶ is independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OR⁸.

In some embodiments of a compound of Formula (I), (II), or (III), A isselected from the group consisting of:

In some embodiments of a compound of Formula (I), (II), or (III), A isselected from the group consisting of:

In some embodiments of a compound of Formula (I), (II), or (III), A is

In some embodiments of a compound of Formula (I), (II), or (III), A is

It is understood that each description of A may be combined with eachdescription of R¹-R⁵ the same as if each and every combination werespecifically and individually listed. It is similarly understood thateach description of A may be combined with each description of B (andfurther with each description of R¹-R⁵) the same as if each and everycombination were specifically and individually listed. For example, inone aspect, it is understood that each description of A may be combinedin one aspect with a variation in which R¹, R³, R⁵ are each hydrogen andone of R² and R⁴ is hydrogen and one of R² and R⁴ is oxo. In one suchvariation, each description of A is combined in one aspect with avariation in which R¹, R², R³, R⁵ are each hydrogen and R⁴ is oxo. Inanother such variation, each description of A is combined in one aspectwith a variation in which R¹, R³, R⁴, R⁵ are each hydrogen and R² isoxo. Such embodiments may further be combined with each description ofB.

In some embodiments of a compound of Formula (I), (II), or (III), B isphenyl, optionally further substituted with R⁷. In some embodiments, Bis 5- to 6-membered heteroaryl optionally further substituted with R⁷.In some embodiments, B is pyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl,isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl, each optionallysubstituted with R⁷. In some embodiments, B is furanyl, pyridinyl,oxazoyl, or oxadiazoyl, each optionally substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), B is a5- to 6-membered carbocycle optionally further substituted with R⁷. Insome embodiments, B is a fully saturated 5- to 6-membered carbocycleoptionally further substituted with R⁷. In some embodiments, B iscyclopentyl or cyclohexyl, optionally further substituted with R⁷. Insome embodiments, B is a 5- to 6-membered carbocycle optionallysubstituted with one or more groups selected from halogen, —CN, —OR⁸,—SR⁸, —NR⁹R¹⁰, —NO₂, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰, —C(O)NR⁸S(O)₂R⁹,—OC(O)R⁸, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸,C₃-C₆ cycloalkyl and C₁-C₆ alkyl optionally substituted by halogen. Insome embodiments, B is a 5- to 6-membered carbocycle optionallysubstituted with halogen.

In some embodiments of a compound of Formula (I), (II), or (III), B is a5- to 6-membered heterocycle optionally further substituted with R⁷. Insome embodiments, B is a fully saturated 5- to 6-membered heterocycleoptionally further substituted with R⁷. In some embodiments, B ispyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl,1,3-dioxolanyl, tetrahydrothiophenyl, oxathiolanyl, sulfolanyl,piperidinyl, piperazinyl, tetrahydropyranyl, dioxanyl, thianyl,dithianyl, trithianyl, morpholinyl, thiomorpholinyl optionally furthersubstituted with R⁷. In some embodiments, B is a 5- to 6-memberedheterocycle optionally substituted with one or more groups selected fromhalogen, —CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰,—C(O)NR⁸S(O)₂R⁹, —OC(O)R⁸, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰,—S(O)R⁸, —S(O)₂R⁸, C₃-C₆ cycloalkyl and C₁-C₆ alkyl optionallysubstituted by halogen. In some embodiments, B is a 5- to 6-memberedheterocycle optionally substituted with halogen.

In some embodiments of a compound of Formula (I), (II), or (III), B is a9- to 10-membered heteroaryl optionally further substituted with R⁷. Insome embodiments, B is selected from the group consisting of pyridyl,quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl,naphthyridinyl, benzoxazolyl, benzothiazolyl, benzoimidazoyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl,oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl,thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzofuranyl, benzoisoxazolyl, benzoxadiazolyl, benzothiophenyl,benzoisothiazolyl, benzothiadiazolyl, pyrrolopyridinyl,pyrazolopyridinyl, imidazopyridinyl, triazolopyridinyl, furopyridinyl,oxazolopyridinyl, isoxazolopyridinyl, oxadiazolopyridinyl,thienopyridinyl, thiazolopyridinyl, isothiazolopyridinyl,thiadiazolopyridinyl, thienopyridinyl, phthalazinyl, pyrazolothiazolyl,pyrazolothiazolyl and imidazothiazolyl, each optionally substituted withR⁷. In one aspect, such groups are unsubstituted. In another aspect,such groups are substituted with 1-3 R⁷, which may be the same ordifferent. In some embodiments, B is a 9- to 10-membered heteroaryloptionally substituted with one or more groups selected from halogen,—CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰,—C(O)NR⁸S(O)₂R⁹, —OC(O)R⁸, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰,—S(O)R⁸, —S(O)₂R⁸, C₃-C₆ cycloalkyl and C₁-C₆ alkyl optionallysubstituted by halogen. In some embodiments, B is a 9- to 10-memberedheteroaryl optionally substituted with halogen.

In some embodiments of a compound of Formula (I), (II), or (III), R⁷ isindependently selected from the group consisting of halogen, —CN, —OR⁸,—SR⁸, —NR⁹R¹⁰, —NO₂, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰, —C(O)NR⁸S(O)₂R⁹,—OC(O)R⁸, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸,C₃-C₆ cycloalkyl and C₁-C₆ alkyl optionally substituted by halogen. Insome embodiments, R⁷ is halogen.

In some embodiments of a compound of Formula (I), (II), or (III), B isselected from the group consisting of:

In some embodiments of a compound of Formula (I), (II), or (III), B isselected from the group consisting of:

In some embodiments of a compound of Formula (I), (II), or (III), B isselected from the group consisting of:

In some embodiments of a compound of Formula (I), (II), or (III), B isselected from

In some embodiments of a compound of Formula (I), (II), or (III), A isC₆-C₁₂ aryl or 5- to 10-membered heteroaryl, each optionally furthersubstituted with R⁶, and B is phenyl or 5- to 6-membered heteroaryl,each optionally further substituted with R⁷. In some embodiments, A isC₆-C₁₂ aryl, optionally further substituted with R⁶, and B is phenyl,optionally further substituted with R⁷. In some embodiments, A is C₆-C₁₂aryl, optionally further substituted with R⁶, and B is 5- to 6-memberedheteroaryl, optionally further substituted with R⁷. In some embodiments,A is 5- to 10-membered heteroaryl, optionally further substituted withR⁶, and B is phenyl, optionally further substituted with R⁷. In someembodiments, A is 5- to 10-membered heteroaryl, optionally furthersubstituted with R⁶, and B is 5- to 6-membered heteroaryl, optionallyfurther substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is9- to 10-membered carbocycle or 9- to 10-membered heterocycle, eachoptionally further substituted with R⁶, and B is phenyl, 5- to6-membered heteroaryl, 5- to 6-membered carbocycle, or 5- to 6-memberedheterocycle, each optionally further substituted with R⁷. In someembodiments, A is 9- to 10-membered carbocycle, optionally furthersubstituted with R⁶, and B is phenyl, optionally further substitutedwith R⁷. In some embodiments, A is 9- to 10-membered carbocycle,optionally further substituted with R⁶, and B is 5- to 6-memberedheteroaryl, optionally further substituted with R⁷. In some embodiments,A is 9- to 10-membered carbocycle, optionally further substituted withR⁶, and B is 5- to 6-membered carbocycle, optionally further substitutedwith R⁷. In some embodiments, A is 9- to 10-membered carbocycle,optionally further substituted with R⁶, and B is 5- to 6-memberedheterocycle, optionally further substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A isC₆-C₁₂ aryl or 5- to 10-membered heteroaryl, each optionally furthersubstituted with R⁶, and B is 5- to 6-membered carbocycle or 5- to6-membered heterocycle, each optionally further substituted with R⁷. Insome embodiments, A is C₆-C₁₂ aryl, optionally further substituted withR⁶, and B is 5- to 6-membered carbocycle, optionally further substitutedwith R⁷. In some embodiments, A is C₆-C₁₂ aryl, optionally furthersubstituted with R⁶, and B is 5- to 6-membered heterocycle, optionallyfurther substituted with R⁷. In some embodiments, A is 5- to 10-memberedheteroaryl, optionally further substituted with R⁶, and B is 5- to6-membered carbocycle, optionally further substituted with R⁷. In someembodiments, A is 5- to 10-membered heteroaryl, optionally furthersubstituted with R⁶, and B is 5- to 6-membered heterocycle, optionallyfurther substituted with R⁷. In some embodiments, when A is phenyl orpyridyl, either of which is optionally further substituted with R⁶, B isnot a saturated heterocycle.

In some embodiments of a compound of Formula (I), (II), or (III), A isC₆-C₁₂ aryl or 5- to 10-membered heteroaryl, each optionally furthersubstituted with R⁶, and B is 9- to 10-membered carbocycle, optionallyfurther substituted with R⁷. In some embodiments, A is C₆-C₁₂ aryl,optionally further substituted with R⁶, and B is 9- to 10-memberedcarbocycle, optionally further substituted with R⁷. In some embodiments,A is 5- to 10-membered heteroaryl, optionally further substituted withR⁶, and B is 9- to 10-membered carbocycle, optionally furthersubstituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f) are eachindependently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen,—CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C═NH(OR⁸), —C(O)R⁸, —OC(O)R⁸, —C(O)OR⁸,—C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)OR⁹, —NR⁸C(O)NR⁹R¹⁰,—S(O)R⁸, —S(O)₂R⁸, —NR⁸S(O)R⁹, —C(O)NR⁸S(O)R⁹, —NR⁸S(O)₂R⁹,—C(O)NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰, —P(O)(OR⁹)(OR¹⁰), C₃-C₆cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl,C₆-C₁₄ aryl, —(C₁-C₃ alkylene)CN, —(C₁-C₃ alkylene)OR⁸, —(C₁-C₃alkylene)SR⁸, —(C₁-C₃ alkylene)NR⁹R¹⁰, —(C₁-C₃ alkylene)CF₃, —(C₁-C₃alkylene)NO₂, —C═NH(OR⁸), —(C₁-C₃ alkylene)C(O)R⁸, —(C₁-C₃alkylene)OC(O)R⁸, —(C₁-C₃ alkylene)C(O)OR⁸, —(C₁-C₃ alkylene)C(O)NR⁹R¹⁰,—(C₁-C₃ alkylene)OC(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)NR⁸C(O)R⁹, —(C₁-C₃alkylene)NR⁸C(O)OR⁹, —(C₁-C₃ alkylene)NR⁸C(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)R⁸, —(C₁-C₃ alkylene)S(O)₂R⁸, —(C₁-C₃ alkylene)NR⁸S(O)R⁹,—C(O)(C₁-C₃ alkylene)NR⁸S(O)R⁹, —(C₁-C₃ alkylene)NR⁸S(O)₂R⁹, —(C₁-C₃alkylene)C(O)NR⁸S(O)₂R⁹, —(C₁-C₃ alkylene)S(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)₂NR⁹R¹⁰, —(C₁-C₃ alkylene)P(O)(OR⁹)(OR¹⁰), —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-12-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-10-membered heteroaryl) or —(C₁-C₃alkylene)(C₆-C₁₄ aryl), wherein each R^(6a), R^(6b), R^(6c), R^(6d),R^(6e), and R^(6f) is independently optionally substituted by halogen,oxo, —OR¹¹, —NR¹¹R¹², —C(O)R¹¹, —CN, —S(O)R¹¹, —S(O)₂R¹¹,—P(O)(OR¹¹)(OR¹²), —(C₁-C₃ alkylene)OR¹¹, —(C₁-C₃ alkylene)NR¹¹R¹²,—(C₁-C₃ alkylene)C(O)R¹¹, —(C₁-C₃ alkylene)S(O)R¹¹, —(C₁-C₃alkylene)S(O)₂R¹¹, —(C₁-C₃ alkylene)P(O)(OR¹¹)(OR¹²), C₃-C₈ cycloalkyl,or C₁-C₆ alkyl optionally substituted by oxo, —OH or halogen.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f) are eachindependently H, C₁-C₆ alkyl, halogen, —CN, or —OC₁-C₆ alkyl. In someembodiments, R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f) are eachH. In some embodiments, one of R^(6a), R^(6b), R^(6c), R^(6d), R^(6e),and R^(6f) is Cl, F, Br, or I. In some embodiments, one of R^(6a),R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f) is Cl. In some embodiments,one of R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f) is halogen andthe others are each H. In some embodiments, one of R^(6a), R^(6b),R^(6c), R^(6d), R^(6e), and R^(6f) is halogen and one of R^(6a), R^(6b),R^(6c), R^(6d), R^(6e), and R^(6f) is C₁-C₆ alkyl. In some embodiments,one of R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f) is Cl and oneof R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f) is methyl. In someembodiments, R^(6a) is C₁-C₆ alkyl. In some embodiments, R^(6b) is C₁-C₆alkyl. In some embodiments, R^(6c) is C₁-C₆ alkyl. In some embodiments,R^(6d) is C₁-C₆ alkyl. In some embodiments, R^(6e) is C₁-C₆ alkyl. Insome embodiments, R^(6f) is C₁-C₆ alkyl. In some embodiments, R^(6a) ismethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, ortertbutyl. In some embodiments, R^(6b) is methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl. In someembodiments, R^(6c) is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, secbutyl, or tertbutyl. In some embodiments, R^(6d) is methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.In some embodiments, R^(6e) is methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, secbutyl, or tertbutyl. In some embodiments, R^(6f)is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, ortertbutyl. In some embodiments, R^(6a) is C₁-C₆ alkyl and R^(6b) ishalogen. In some embodiments, R^(6a) is C₁-C₆ alkyl and R^(6c) ishalogen. In some embodiments, R^(6a) is C₁-C₆ alkyl and R^(6d) ishalogen. In some embodiments, R^(6a) is C₁-C₆ alkyl and R^(6e) ishalogen. In some embodiments, R^(6a) is C₁-C₆ alkyl and R^(6f) ishalogen. In some embodiments, R^(6b) is C₁-C₆ alkyl and R^(6a) ishalogen. In some embodiments, R^(6b) is C₁-C₆ alkyl and R^(6c) ishalogen. In some embodiments, R^(6b) is C₁-C₆ alkyl and R^(6d) ishalogen. In some embodiments, R^(6b) is C₁-C₆ alkyl and R^(6e) ishalogen. In some embodiments, R^(6b) is C₁-C₆ alkyl and R^(6f) ishalogen. In some embodiments, R^(6c) is C₁-C₆ alkyl and R^(6a) ishalogen. In some embodiments, R^(6c) is C₁-C₆ alkyl and R^(6b) ishalogen. In some embodiments, R^(6c) is C₁-C₆ alkyl and R^(6d) ishalogen. In some embodiments, R^(6c) is C₁-C₆ alkyl and R^(6e) ishalogen. In some embodiments, R^(6c) is C₁-C₆ alkyl and R^(6f) ishalogen. In some embodiments, R^(6d) is C₁-C₆ alkyl and R^(6a) ishalogen. In some embodiments, R^(6d) is C₁-C₆ alkyl and R^(6b) ishalogen. In some embodiments, R^(6d) is C₁-C₆ alkyl and R^(6c) ishalogen. In some embodiments, R^(6d) is C₁-C₆ alkyl and R^(6e) ishalogen. In some embodiments, R^(6d) is C₁-C₆ alkyl and R^(6f) ishalogen. In some embodiments, R^(6e) is C₁-C₆ alkyl and R^(6a) ishalogen. In some embodiments, R^(6e) is C₁-C₆ alkyl and R^(6b) ishalogen. In some embodiments, R^(6e) is C₁-C₆ alkyl and R^(6c) ishalogen. In some embodiments, R^(6e) is C₁-C₆ alkyl and R^(6d) ishalogen. In some embodiments, R^(6e) is C₁-C₆ alkyl and R^(6f) ishalogen. In some embodiments, R^(6f) is C₁-C₆ alkyl and R^(6a) ishalogen. In some embodiments, R^(6f) is C₁-C₆ alkyl and R^(6b) ishalogen. In some embodiments, R^(6f) is C₁-C₆ alkyl and R^(6c) ishalogen. In some embodiments, R^(6f) is C₁-C₆ alkyl and R^(6d) ishalogen. In some embodiments, R^(6f) is C₁-C₆ alkyl and R^(6e) ishalogen. In some embodiments, two of R^(6a), R^(6b), R^(6c), R^(6d),R^(6e), and R^(6f) are halogen. In some embodiments, two of R^(6a),R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f) are C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b),R^(6c), R^(6d), R^(6e), and R^(6f) are each H; and B is phenyl,optionally substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b),R^(6c), R^(6d), R^(6e), and R^(6f) are each H; and B is a 5- to6-membered carbocycle, optionally substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b),R^(6c), R^(6d), R^(6e), and R^(6f) are each H; and B is a 5- to6-membered heterocycle, optionally substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b),R^(6c), R^(6d), R^(6e), and R^(6f) are each H; and B is a 5- to6-membered heterocycle, optionally substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b),R^(6c), R^(6d), R^(6e), and R^(6f) are each H; and B is a 9- to10-membered heteroaryl, optionally substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b),R^(6c), R^(6e), and R^(6f) are each H; and B is selected from the groupconsisting of:

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b),R^(6c), R^(6d), R^(6e), and R^(6f) are each H; and B is selected fromthe group consisting of:

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b),R^(6c), R^(6d), R^(6e), and R^(6f) are each H; and B is selected fromthe group consisting of

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and theremainder of R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f) are eachH; and B is selected from and

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein R^(6b), R^(6e), R^(6d), R^(6e), R^(6f), and R^(6g) are eachindependently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halogen,—CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C═NH(OR⁸), —C(O)R⁸, —OC(O)R⁸, —C(O)OR⁸,—C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)OR⁹, —NR⁸C(O)NR⁹R¹⁰,—S(O)R⁸, —S(O)₂R⁸, —NR⁸S(O)R⁹, —C(O)NR⁸S(O)R⁹, —NR⁸S(O)₂R⁹,—C(O)NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰, —P(O)(OR⁹)(OR¹⁰), C₃-C₆cycloalkyl, 3-12-membered heterocyclyl, 5- to 10-membered heteroaryl,C₆-C₁₄ aryl, —(C₁-C₃ alkylene)CN, —(C₁-C₃ alkylene)OR⁸, —(C₁-C₃alkylene)SR⁸, —(C₁-C₃ alkylene)NR⁹R¹⁰, —(C₁-C₃ alkylene)CF₃, —(C₁-C₃alkylene)NO₂, —C═NH(OR⁸), —(C₁-C₃ alkylene)C(O)R⁸, —(C₁-C₃alkylene)OC(O)R⁸, —(C₁-C₃ alkylene)C(O)OR⁸, —(C₁-C₃ alkylene)C(O)NR⁹R¹⁰,—(C₁-C₃ alkylene)OC(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)NR⁸C(O)R⁹, —(C₁-C₃alkylene)NR⁸C(O)OR⁹, —(C₁-C₃ alkylene)NR⁸C(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)R⁸, —(C₁-C₃ alkylene)S(O)₂R⁸, —(C₁-C₃ alkylene)NR⁸S(O)R⁹,—C(O)(C₁-C₃ alkylene)NR⁸S(O)R⁹, —(C₁-C₃ alkylene)NR⁸S(O)₂R⁹, —(C₁-C₃alkylene)C(O)NR⁸S(O)₂R⁹, —(C₁-C₃ alkylene)S(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)₂NR⁹R¹⁰, —(C₁-C₃ alkylene)P(O)(OR⁹)(OR¹⁰), —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-12-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-10-membered heteroaryl) or —(C₁-C₃alkylene)(C₆-C₁₄ aryl), wherein each R^(6b), R^(6c), R^(6d), R^(6e),R^(6f), and R^(6g) is independently optionally substituted by halogen,oxo, —OR¹¹, —NR¹¹R¹², —C(O)R¹¹, —CN, —S(O)R¹¹, —S(O)₂R¹¹,—P(O)(OR¹¹)(OR¹²), —(C₁-C₃ alkylene)OR¹¹, —(C₁-C₃ alkylene)NR¹¹R¹²,—(C₁-C₃ alkylene)C(O)R¹¹, —(C₁-C₃ alkylene)S(O)R¹¹, —(C₁-C₃alkylene)S(O)₂R¹¹, —(C₁-C₃ alkylene)P(O)(OR¹¹)(OR¹²), C₃-C₈ cycloalkyl,or C₁-C₆ alkyl optionally substituted by oxo, —OH or halogen.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g) are eachindependently H, C₁-C₆ alkyl, halogen, —CN, or —OC₁-C₆ alkyl. In someembodiments, R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g) are eachH. In some embodiments, one of R^(6b), R^(6c), R^(6d), R^(6e), R^(6f),and R^(6g) is Cl, F, Br, or I. In some embodiments, one of R^(6b),R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g) is Cl. In some embodiments,one of R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g) is halogen andthe others are each H. In some embodiments, one of R^(6b), R^(6c),R^(6d), R^(6e), R^(6f), and R^(6g) is halogen and one of R^(6b), R^(6c),R^(6d), R^(6e), R^(6f), and R^(6g) is C₁-C₆ alkyl. In some embodiments,one of R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g) is Cl and oneof R^(6b), R^(6c), R^(6d), R^(6e), R^(6f) and R^(6g) is methyl. In someembodiments, R^(6g) is C₁-C₆ alkyl. In some embodiments, R^(6b) is C₁-C₆alkyl. In some embodiments, R^(6c) is C₁-C₆ alkyl. In some embodiments,R^(6d) is C₁-C₆ alkyl. In some embodiments, R^(6e) is C₁-C₆ alkyl. Insome embodiments, R^(6f) is C₁-C₆ alkyl. In some embodiments, R^(6g) ismethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, ortertbutyl. In some embodiments, R^(6b) is methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl. In someembodiments, R^(6c) is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, secbutyl, or tertbutyl. In some embodiments, R^(6d) is methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.In some embodiments, R^(6e) is methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, secbutyl, or tertbutyl. In some embodiments, R^(6f)is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, ortertbutyl. In some embodiments, R^(6g) is C₁-C₆ alkyl and R^(6b) ishalogen. In some embodiments, R^(6g) is C₁-C₆ alkyl and R^(6c) ishalogen. In some embodiments, R^(6g) is C₁-C₆ alkyl and R^(6d) ishalogen. In some embodiments, R^(6g) is C₁-C₆ alkyl and R^(6e) ishalogen. In some embodiments, R^(6g) is C₁-C₆ alkyl and R^(6f) ishalogen. In some embodiments, R^(6b) is C₁-C₆ alkyl and R^(6g) ishalogen. In some embodiments, R^(6b) is C₁-C₆ alkyl and R^(6c) ishalogen. In some embodiments, R^(6b) is C₁-C₆ alkyl and R^(6d) ishalogen. In some embodiments, R^(6b) is C₁-C₆ alkyl and R^(6e) ishalogen. In some embodiments, R^(6b) is C₁-C₆ alkyl and R^(6f) ishalogen. In some embodiments, R^(6c) is C₁-C₆ alkyl and R^(6g) ishalogen. In some embodiments, R^(6c) is C₁-C₆ alkyl and R^(6b) ishalogen. In some embodiments, R^(6c) is C₁-C₆ alkyl and R^(6d) ishalogen. In some embodiments, R^(6c) is C₁-C₆ alkyl and R^(6e) ishalogen. In some embodiments, R^(6c) is C₁-C₆ alkyl and R^(6f) ishalogen. In some embodiments, R^(6d) is C₁-C₆ alkyl and R^(6g) ishalogen. In some embodiments, R^(6d) is C₁-C₆ alkyl and R^(6b) ishalogen. In some embodiments, R^(6d) is C₁-C₆ alkyl and R^(6c) ishalogen. In some embodiments, R^(6d) is C₁-C₆ alkyl and R^(6e) ishalogen. In some embodiments, R^(6d) is C₁-C₆ alkyl and R^(6f) ishalogen. In some embodiments, R^(6e) is C₁-C₆ alkyl and R^(6g) ishalogen. In some embodiments, R^(6e) is C₁-C₆ alkyl and R^(6b) ishalogen. In some embodiments, R^(6e) is C₁-C₆ alkyl and R^(6c) ishalogen. In some embodiments, R^(6e) is C₁-C₆ alkyl and R^(6d) ishalogen. In some embodiments, R^(6e) is C₁-C₆ alkyl and R^(6f) ishalogen. In some embodiments, R^(6f) is C₁-C₆ alkyl and R^(6g) ishalogen. In some embodiments, R^(6f) is C₁-C₆ alkyl and R^(6b) ishalogen. In some embodiments, R^(6f) is C₁-C₆ alkyl and R^(6c) ishalogen. In some embodiments, R^(6f) is C₁-C₆ alkyl and R^(6d) ishalogen. In some embodiments, R^(6f) is C₁-C₆ alkyl and R^(6e) ishalogen. In some embodiments, two of R^(6b), R^(6c), R^(6d), R^(6e),R^(6f), and R^(6g) are halogen. In some embodiments, two of R^(6b),R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g) are C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6b), R^(6c),R^(6d), R^(6e), R^(6f), and R^(6g) are each H; and B is phenyl,optionally substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6b), R^(6c),R^(6d), R^(6e), R^(6f), and R^(6g) are each H; and B is a 5- to6-membered heteroaryl, optionally substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6b), R^(6c),R^(6d), R^(6e), R^(6f), and R^(6g) are each H; and B is a 5- to6-membered carbocycle, optionally substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6b), R^(6c),R^(6d), R^(6e), R^(6f), and R^(6g) are each H; and B is a 5- to6-membered heterocycle, optionally substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6b), R^(6c),R^(6d), R^(6e), R^(6f), and R^(6g) are each H; and B is a 9- to10-membered heteroaryl, optionally substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6b), R^(6c),R^(6d), R^(6e), R^(6f), and R^(6g) are each H; and B is selected fromthe group consisting of:

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6b), R^(6c),R^(6d), R^(6e), R^(6f), and R^(6g) are each H; and B is selected fromthe group consisting of:

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6b), R^(6c),R^(6d), R^(6e), R^(6f), and R^(6g) are each H; and B is selected fromthe group consisting of

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g)are independently selected from the group consisting of C₁-C₆ alkyl,halogen, —CN, and —OC₁-C₆ alkyl, and the remainder of R^(6b), R^(6c),R^(6d), R^(6e), R^(6f), and R^(6g) are each H; and B is selected from

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein X¹ is selected from the group consisting of N, C, and CH; X² isselected from the group consisting of NH, O, and S; and R^(6a), R^(6b),and R^(6c) are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, halogen, —CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C═NH(OR⁸), —C(O)R⁸,—OC(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)OR⁹,—NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, —NR⁸S(O)R⁹, —C(O)NR⁸S(O)R⁹,—NR⁸S(O)₂R⁹, —C(O)NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰,—P(O)(OR⁹)(OR¹⁰), C₃-C₆ cycloalkyl, 3-12-membered heterocyclyl, 5- to10-membered heteroaryl, C₆-C₁₄ aryl, —(C₁-C₃ alkylene)CN, —(C₁-C₃alkylene)OR⁸, —(C₁-C₃ alkylene)SR⁸, —(C₁-C₃ alkylene)NR⁹R¹⁰, —(C₁-C₃alkylene)CF₃, —(C₁-C₃ alkylene)NO₂, —C═NH(OR⁸), —(C₁-C₃ alkylene)C(O)R⁸,—(C₁-C₃ alkylene)OC(O)R⁸, —(C₁-C₃ alkylene)C(O)OR⁸, —(C₁-C₃alkylene)C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)OC(O)NR⁹R¹⁰, —(C₁-C₃alkylene)NR⁸C(O)R⁹, —(C₁-C₃ alkylene)NR⁸C(O)OR⁹, —(C₁-C₃alkylene)NR⁸C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)S(O)R⁸, —(C₁-C₃alkylene)S(O)₂R⁸, —(C₁-C₃ alkylene)NR⁸S(O)R⁹, —C(O)(C₁-C₃alkylene)NR⁸S(O)R⁹, —(C₁-C₃ alkylene)NR⁸S(O)₂R⁹, —(C₁-C₃alkylene)C(O)NR⁸S(O)₂R⁹, —(C₁-C₃ alkylene)S(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)₂NR⁹R¹⁰, —(C₁-C₃ alkylene)P(O)(OR⁹)(OR¹⁰), —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-12-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-10-membered heteroaryl) or —(C₁-C₃alkylene)(C₆-C₁₄ aryl), wherein each R^(6a), R^(6b), and R^(6c) isindependently optionally substituted by halogen, oxo, —OR, —NR¹¹R¹²,—C(O)R¹¹, —CN, —S(O)R¹¹, —S(O)₂R¹¹, —P(O)(OR¹¹)(OR¹²), —(C₁-C₃alkylene)OR¹¹, —(C₁-C₃ alkylene)NR¹¹R¹², —(C₁-C₃ alkylene)C(O)R¹¹,—(C₁-C₃ alkylene)S(O)R¹¹, —(C₁-C₃ alkylene)S(O)₂R¹¹, —(C₁-C₃alkylene)P(O)(OR)(OR¹²), C₃-C₈ cycloalkyl, or C₁-C₆ alkyl optionallysubstituted by oxo, —OH or halogen.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein X¹ is selected from the group consisting of N, C, and CH; X² isselected from the group consisting of NH, O, and S; and R^(6a), R^(6b),and R^(6c) are each independently H, C₁-C₆ alkyl, halogen, —CN, or—OC₁-C₆ alkyl. In some embodiments of a compound of Formula (I), (II),or (III), A is H

In some embodiments, R^(6a), R^(6b), and R^(6c) are each H. In someembodiments, one of R^(6a), R^(6b), and R^(6c) is Cl, F, Br, or I. Insome embodiments, one of R^(6a), R^(6b), and R^(6c) is Cl. In someembodiments, one of R^(6a), R^(6b), and R^(6c) is halogen and the othersare each H. In some embodiments, one of R^(6a), R^(6b), and R^(6c) ishalogen and one of R^(6a), R^(6b), and R^(6c) is C₁-C₆ alkyl. In someembodiments, one of R^(6a), R^(6b), and R^(6c) is Cl and one of R^(6a),R^(6b), and R^(6c) is methyl. In some embodiments, R^(6a) is C₁-C₆alkyl. In some embodiments, R^(6b) is C₁-C₆ alkyl. In some embodiments,R^(6c) is C₁-C₆ alkyl. In some embodiments, R^(6a) is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl. In someembodiments, R^(6b) is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, secbutyl, or tertbutyl. In some embodiments, R^(6c) is methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.In some embodiments, R^(6a) is C₁-C₆ alkyl and R^(6b) is halogen. Insome embodiments, R^(6a) is C₁-C₆ alkyl and R^(6c) is halogen. In someembodiments, R^(6b) is C₁-C₆ alkyl and R^(6a) is halogen. In someembodiments, R^(6b) is C₁-C₆ alkyl and R^(6c) is halogen. In someembodiments, R^(6c) is C₁-C₆ alkyl and R^(6a) is halogen. In someembodiments, R^(6c) is C₁-C₆ alkyl and R^(6b) is halogen. In someembodiments, two of R^(6a), R^(6b), and R^(6c) are halogen. In someembodiments, two of R^(6a), R^(6b), and R^(6c) are C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b), and R^(6c) are eachH; and B is phenyl, optionally substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b), and R^(6c) are eachH; and B is a 5- to 6-membered heteroaryl, optionally substituted withR⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b), and R^(6c) are eachH; and B is a 5- to 6-membered carbocycle, optionally substituted withR⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b), and R^(6c) are eachH; and B is a 5- to 6-membered heterocycle, optionally substituted withR⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b), and R^(6c) are eachH; and B is a 9- to 10-membered heteroaryl, optionally substituted withR⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b), and R^(6c) are eachH; and B is selected from the group consisting of:

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b), and R^(6c) are eachH; and B is selected from the group consisting of:

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b), and R^(6c) are eachH; and B is selected from the group consisting of

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6a), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6a), R^(6b), and R^(6c) are eachH; and B is selected from

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein X¹ is selected from the group consisting of N, C, and CH; X² isselected from the group consisting of NH, O, and S; and R^(6g), R^(6b),and R^(6c) are each independently H, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, halogen, —CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C═NH(OR⁸), —C(O)R⁸,—OC(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)OR⁹,—NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, —NR⁸S(O)R⁹, —C(O)NR⁸S(O)R⁹,—NR⁸S(O)₂R⁹, —C(O)NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰,—P(O)(OR⁹)(OR¹⁰), C₃-C₆ cycloalkyl, 3-12-membered heterocyclyl, 5- to10-membered heteroaryl, C₆-C₁₄ aryl, —(C₁-C₃ alkylene)CN, —(C₁-C₃alkylene)OR⁸, —(C₁-C₃ alkylene)SR⁸, —(C₁-C₃ alkylene)NR⁹R¹⁰, —(C₁-C₃alkylene)CF₃, —(C₁-C₃ alkylene)NO₂, —C═NH(OR⁸), —(C₁-C₃ alkylene)C(O)R⁸,—(C₁-C₃ alkylene)OC(O)R⁸, —(C₁-C₃ alkylene)C(O)OR⁸, —(C₁-C₃alkylene)C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)OC(O)NR⁹R¹⁰, —(C₁-C₃alkylene)NR⁸C(O)R⁹, —(C₁-C₃ alkylene)NR⁸C(O)OR⁹, —(C₁-C₃alkylene)NR⁸C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)S(O)R⁸, —(C₁-C₃alkylene)S(O)₂R⁸, —(C₁-C₃ alkylene)NR⁸S(O)R⁹, —C(O)(C₁-C₃alkylene)NR⁸S(O)R⁹, —(C₁-C₃ alkylene)NR⁸S(O)₂R⁹, —(C₁-C₃alkylene)C(O)NR⁸S(O)₂R⁹, —(C₁-C₃ alkylene)S(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)₂NR⁹R¹⁰, —(C₁-C₃ alkylene)P(O)(OR⁹)(OR¹⁰), —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-12-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-10-membered heteroaryl) or —(C₁-C₃alkylene)(C₆-C₁₄ aryl), wherein each R^(6g), R^(6b), and R^(6c) isindependently optionally substituted by halogen, oxo, —OR¹¹, —NR¹¹R¹²,—C(O)R¹¹, —CN, —S(O)R¹¹, —S(O)₂R¹¹, —P(O)(OR¹¹)(OR¹²), —(C₁-C₃alkylene)OR¹¹, —(C₁-C₃ alkylene)NR¹¹R¹², —(C₁-C₃ alkylene)C(O)R¹¹,—(C₁-C₃ alkylene)S(O)R¹¹, —(C₁-C₃ alkylene)S(O)₂R¹¹, —(C₁-C₃alkylene)P(O)(OR)(OR¹²), C₃-C₈ cycloalkyl, or C₁-C₆ alkyl optionallysubstituted by oxo, —OH or halogen.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein X¹ is selected from the group consisting of N, C, and CH; X² isselected from the group consisting of NH, O, and S; and R^(6g), R^(6b),and R^(6c) are each independently H, C₁-C₆ alkyl, halogen, —CN, or—OC₁-C₆ alkyl. In some embodiments of a compound of Formula (I), (II),or (III), A is

In some embodiments, R^(6g), R^(6b), and R^(6c) are each H. In someembodiments, one of R^(6g), R^(6b), and R^(6c) is Cl, F, Br, or I. Insome embodiments, one of R^(6g), R^(6b), and R^(6c) is Cl. In someembodiments, one of R^(6g), R^(6b), and R^(6c) is halogen and the othersare each H. In some embodiments, one of R^(6g), R^(6b), and R^(6c) ishalogen and one of R^(6g), R^(6b), and R^(6c) is C₁-C₆ alkyl. In someembodiments, one of R^(6g), R^(6b), and R^(6c) is Cl and one of R^(6g),R^(6b), and R^(6c) is methyl. In some embodiments, R^(6g) is C₁-C₆alkyl. In some embodiments, R^(6b) is C₁-C₆ alkyl. In some embodiments,R^(6c) is C₁-C₆ alkyl. In some embodiments, R^(6g) is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl. In someembodiments, R^(6b) is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, secbutyl, or tertbutyl. In some embodiments, R^(6c) is methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secbutyl, or tertbutyl.In some embodiments, R^(6g) is C₁-C₆ alkyl and R^(6b) is halogen. Insome embodiments, R^(6g) is C₁-C₆ alkyl and R^(6c) is halogen. In someembodiments, R^(6b) is C₁-C₆ alkyl and R^(6g) is halogen. In someembodiments, R^(6b) is C₁-C₆ alkyl and R^(6c) is halogen. In someembodiments, R^(6c) is C₁-C₆ alkyl and R^(6g) is halogen. In someembodiments, R^(6c) is C₁-C₆ alkyl and R^(6b) is halogen. In someembodiments, two of R^(6g), R^(6b), and R^(6c) are halogen. In someembodiments, two of R^(6g), R^(6b), and R^(6c) are C₁-C₆ alkyl.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6b), and R^(6c) are independently selected fromthe group consisting of C₁-C₆ alkyl, halogen, —CN, and —OC₁-C₆ alkyl,and the remainder of R^(6g), R^(6b), and R^(6c) are each H; and B isphenyl, optionally substituted with R⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6g), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6g), R^(6b), and R^(6c) are eachH; and B is a 5- to 6-membered carbocycle, optionally substituted withR⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6g), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6g), R^(6b), and R^(6c) are eachH; and B is a 5- to 6-membered heterocycle, optionally substituted withR⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6g), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6g), R^(6b), and R^(6c) are eachH; and B is a 9- to 10-membered heteroaryl, optionally substituted withR⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6g), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6g), R^(6b), and R^(6c) are eachH; and B is a 9- to 10-membered heteroaryl, optionally substituted withR⁷.

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6g), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6g), R^(6b), and R^(6c) are eachH; and B is selected from the group consisting of:

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6g), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6g), R^(6b), and R^(6c) are eachH; and B is selected from the group consisting of:

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6g), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6g), R^(6b), and R^(6c) are eachH; and B is selected from the group consisting of

In some embodiments of a compound of Formula (I), (II), or (III), A is

wherein one or two of R^(6g), R^(6b), and R^(6c) are independentlyselected from the group consisting of C₁-C₆ alkyl, halogen, —CN, and—OC₁-C₆ alkyl, and the remainder of R^(6g), R^(6b), and R^(6c) are eachH; and B is selected from

Also provided are salts of compounds referred to herein, such aspharmaceutically acceptable salts. The invention also includes any orall of the stereochemical forms, including any enantiomeric ordiastereomeric forms, and any tautomers or other forms of the compoundsdescribed.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form. Unlessotherwise stated, “substantially pure” intends a composition thatcontains no more than 35% impurity, wherein the impurity denotes acompound other than the compound comprising the majority of thecomposition or a salt thereof. In some embodiments, a composition ofsubstantially pure compound or a salt thereof is provided wherein thecomposition contains no more than 25%, 20%, 15%, 10%, or 5% impurity. Insome embodiments, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 3%,2%, 1% or 0.5% impurity.

Representative compounds are listed in Table 1. It is understood thatindividual enantiomers and diastereomers if not depicted are embracedherein and their corresponding structures can be readily determinedtherefrom.

TABLE 1 Compound No. Compound 1.1

1.2

1.3

1.4

1.5

1.6

1.7

1.8

1.9

1.10

1.11

1.12

1.13

1.14

1.15

1.16

1.17

1.18

1.19

1.20

1.21

1.22

1.23

1.24

1.25

1.26

1.27

1.28

1.29

1.30

1.31

1.32

1.33

1.34

1.35

1.36

1.37

1.38

1.39

1.40

1.41

1.42

1.43

1.44

1.45

1.46

1.47

1.48

1.49

1.50

1.51

1.52

1.53

1.54

1.55

1.56

1.57

1.58

1.59

1.60

1.61

1.62

1.63

1.64

1.65

1.66

1.67

1.68

1.69

1.70

1.71

1.72

1.73

1.74

1.75

1.76

1.77

1.78

1.79

1.80

1.81

1.82

1.83

1.84

1.85

1.86

1.87

1.88

1.89

1.90

1.91

1.92

1.93

1.94

1.95

1.96

1.97

1.98

1.99

1.100

1.101

1.102

1.103

1.104

1.105

1.106

1.107

1.108

1.109

1.110

1.111

1.112

1.113

1.114

1.115

1.116

1.117

1.118

1.119

1.120

1.121

1.122

1.123

1.124

1.125

1.126

1.127

1.128

1.129

1.130

1.131

1.132

1.133

1.134

1.135

1.136

1.137

1.138

1.139

1.140

1.141

1.142

1.143

1.144

1.145

1.146

1.147

1.148

1.149

1.150

1.151

1.152

1.153

1.154

1.155

1.156

1.157

1.158

1.159

1.160

1.161

1.162

1.163

1.164

1.165

1.166

1.167

1.168

1.169

1.170

1.171

1.172

1.173

1.174

1.175

1.176

1.177

1.178

1.179

1.180

1.181

1.182

1.183

1.184

1.185

1.186

1.187

1.188

1.189

1.190

1.191

1.192

1.193

1.194

1.195

1.196

1.197

1.198

1.199

1.200

1.201

1.202

1.203

1.204

1.205

1.206

1.207

1.208

1.209

1.210

1.211

1.212

1.213

1.214

1.215

1.216

1.217

1.218

1.219

1.220

1.221

1.222

1.223

1.224

1.225

1.226

1.227

1.228

1.229

1.230

1.231

1.232

1.233

1.234

1.235

1.236

1.237

1.238

1.239

1.240

1.241

1.242

1.243

1.244

1.245

1.246

1.247

1.248

1.249

1.250

1.251

1.252

1.253

1.254

1.255

1.256

1.257

1.258

1.259

1.260

1.261

1.262

1.263

1.264

1.265

1.266

1.267

1.268

1.269

1.270

1.271

1.272

1.273

1.274

1.275

1.276

1.277

1.278

1.279

1.280

1.281

1.282

1.283

1.284

1.285

1.286

1.287

1.288

1.289

1.290

1.291

1.292

1.293

1.294

1.295

1.296

1.297

1.298

1.299

1.300

1.301

1.302

1.303

1.304

1.305

1.306

1.307

1.308

1.309

1.310

1.311

1.312

1.313

1.314

1.315

1.316

1.317

1.318

1.319

1.320

1.321

1.322

1.323

1.324

1.325

1.326

1.327

1.328

1.329

1.330

1.331

1.332

1.333

1.334

1.335

1.336

1.337

1.338

1.339

1.340

1.341

1.342

1.343

1.344

1.345

1.346

1.347

1.348

1.349

1.350

1.351

1.352

1.353

1.354

1.355

1.356

1.357

1.358

1.359

1.360

1.361

1.362

1.363

1.364

1.365

1.366

1.367

1.368

1.369

1.370

1.371

1.372

1.373

1.374

1.375

1.376

1.377

1.378

1.379

1.380

1.381

1.382

1.383

1.384

1.385

1.386

1.387

1.388

1.389

1.390

1.391

1.392

1.393

1.394

1.395

1.396

1.397

1.398

1.399

1.400

1.401

1.402

1.403

1.404

1.405

1.406

1.407

1.408

1.409

1.410

1.411

1.412

1.413

1.414

1.415

1.416

1.417

1.418

1.419

1.420

1.421

1.422

1.423

1.424

1.425

1.426

1.427

1.428

1.429

1.430

1.431

1.432

1.433

1.434

1.435

1.436

1.437

1.438

1.439

1.440

1.441

1.442

1.443

1.444

1.445

1.446

1.447

1.448

1.449

1.450

1.451

1.452

1.453

1.454

1.455

1.456

1.457

1.458

1.459

1.460

1.461

1.462

1.463

1.464

1.465

1.466

1.467

1.468

1.469

1.470

1.471

1.472

1.473

1.474

1.475

1.476

1.477

1.478

1.479

1.480

1.481

1.482

1.483

1.484

1.485

1.486

1.487

1.488

1.489

1.490

1.491

1.492

1.493

1.494

1.495

1.496

1.497

1.498

1.499

1.500

1.501

1.502

1.503

1.504

1.505

1.506

1.507

1.508

1.509

1.510

1.511

1.512

1.513

1.514

1.515

1.516

1.517

1.518

1.519

1.520

1.521

1.522

1.523

1.524

1.525

1.526

1.527

1.528

1.529

1.530

1.531

1.532

1.533

1.534

1.535

1.536

1.537

1.538

1.539

1.540

1.541

1.542

1.543

1.544

1.545

1.546

1.547

1.548

1.549

1.550

1.551

1.552

1.553

1.554

1.555

1.556

1.557

1.558

1.559

1.560

1.561

1.562

1.563

1.564

1.565

1.566

1.567

1.568

1.569

1.570

1.571

1.572

1.573

1.574

1.575

1.576

1.577

1.578

1.579

1.580

1.581

1.582

1.583

1.584

1.585

1.586

1.587

1.588

1.589

1.590

1.591

1.592

1.593

1.594

1.595

1.596

1.597

1.598

1.599

1.600

1.601

1.602

1.603

1.604

1.605

1.606

1.607

1.608

1.609

1.610

1.611

1.612

1.613

1.614

1.615

1.616

1.617

1.618

1.619

1.620

1.621

1.622

1.623

1.624

1.625

1.626

1.627

1.628

1.629

1.630

1.631

1.632

1.633

1.634

1.635

1.636

1.637

1.638

1.639

1.640

1.641

1.642

1.643

1.644

1.645

1.646

1.647

1.648

1.649

1.650

1.651

1.652

1.653

1.654

1.655

1.656

1.657

1.658

1.659

1.660

1.661

1.662

1.663

1.664

1.665

1.666

1.667

1.668

1.669

1.670

1.671

1.672

1.673

1.674

1.675

1.676

1.677

1.678

1.679

1.680

1.681

1.682

1.683

1.684

1.685

1.686

1.687

1.688

1.689

1.690

1.691

1.692

1.693

1.694

1.695

1.696

1.697

1.698

1.699

1.700

1.701

1.702

1.703

1.704

1.705

1.706

1.707

1.708

1.709

1.710

1.711

1.712

1.713

1.714

1.715

1.716

1.717

1.718

1.719

1.720

1.721

1.722

1.723

1.724

1.725

1.726

1.727

1.728

1.729

1.730

1.731

1.732

1.733

1.734

1.735

1.736

1.737

1.738

1.739

1.740

1.741

1.742

1.743

1.744

1.745

1.746

1.747

1.748

1.749

1.750

1.751

1.752

1.753

1.754

1.755

1.756

1.757

1.758

1.759

1.760

1.761

1.762

1.763

1.764

1.765

1.766

1.767

1.768

1.769

1.770

1.771

1.772

1.773

1.774

1.775

1.776

1.777

1.778

1.779

1.780

1.781

1.782

1.783

1.784

1.785

1.786

1.787

1.788

1.789

1.790

1.791

1.792

1.793

1.794

1.795

1.796

1.797

1.798

1.799

1.800

1.801

1.802

1.803

1.804

1.805

1.806

1.807

1.808

1.809

1.810

1.811

1.812

1.813

1.814

1.815

1.816

1.817

1.818

1.819

1.820

1.821

1.822

1.823

1.824

1.825

1.826

1.827

1.828

1.829

1.830

1.831

1.832

1.833

1.834

1.835

1.836

1.837

1.838

1.839

1.840

1.841

1.842

1.843

1.844

1.845

1.846

1.847

1.848

1.849

1.850

1.851

1.852

1.853

1.854

1.855

1.856

1.857

1.858

1.859

1.860

1.861

1.862

1.863

1.864

1.865

1.866

1.867

1.868

1.869

1.870

1.871

1.872

1.873

1.874

1.875

1.876

1.877

1.878

1.879

1.880

1.881

1.882

1.883

1.884

1.885

1.886

1.887

1.888

1.889

1.890

1.891

1.892

1.893

1.894

1.895

1.896

1.897

1.898

1.899

1.900

1.901

1.902

1.903

1.904

1.905

1.906

1.907

1.908

1.909

1.910

1.911

1.912

1.913

1.914

1.915

1.916

1.917

1.918

1.919

1.920

1.921

1.922

1.923

1.924

1.925

1.926

1.927

1.928

1.929

1.930

1.931

1.932

1.933

1.934

1.935

1.936

1.937

1.938

1.939

1.940

1.941

1.942

1.943

1.944

1.945

1.946

1.947

1.948

1.949

1.950

1.951

1.952

1.953

1.954

1.955

1.956

1.957

1.958

1.959

1.960

1.961

1.962

1.963

1.964

1.965

1.966

1.967

1.968

1.969

1.970

1.971

1.972

1.973

1.974

1.975

1.976

1.977

1.978

1.979

1.980

1.981

1.982

1.983

1.984

1.985

1.986

1.987

1.988

1.989

1.990

1.991

1.992

1.993

1.994

1.995

1.996

1.997

1.998

1.999

2.000

2.001

2.002

2.003

2.004

2.005

2.006

2.007

2.008

2.009

2.010

2.011

2.012

2.013

2.014

2.015

2.016

2.017

2.018

2.019

2.020

2.021

2.022

2.023

2.024

2.025

2.026

2.027

2.028

2.029

2.030

2.031

2.032

2.033

2.034

2.035

2.036

2.037

2.038

2.039

2.040

2.041

2.042

2.043

In some embodiments, provided herein are compounds described in Table 1,or a tautomer or isomer thereof, or a pharmaceutically acceptable saltof any of the foregoing, and uses thereof.

The embodiments and variations described herein are suitable forcompounds of any formulae detailed herein, where applicable.

Representative examples of compounds detailed herein, includingintermediates and final compounds according to the present disclosureare depicted herein. It is understood that in one aspect, any of thecompounds may be used in the methods detailed herein, including, whereapplicable, intermediate compounds that may be isolated and administeredto an individual.

The compounds depicted herein may be present as salts even if salts arenot depicted and it is understood that the present disclosure embracesall salts and solvates of the compounds depicted here, as well as thenon-salt and non-solvate form of the compound, as is well understood bythe skilled artisan. In some embodiments, the salts of the compoundsprovided herein are pharmaceutically acceptable salts. Where one or moretertiary amine moiety is present in the compound, the N-oxides are alsoprovided and described.

Where tautomeric forms may be present for any of the compounds describedherein, each and every tautomeric form is intended even though only oneor some of the tautomeric forms may be explicitly depicted. Thetautomeric forms specifically depicted may or may not be the predominantforms in solution or when used according to the methods describedherein.

The present disclosure also includes any or all of the stereochemicalforms, including any enantiomeric or diastereomeric forms of thecompounds described. The structure or name is intended to embrace allpossible isomers of a compound depicted.

Additionally, the structure or name is intended to embrace tautomericforms of the compounds described herein. For example, when R¹ ishydrogen, the tautomer of Formula (II) is Formula (IIa):

Similarly, when R¹ is hydrogen, the tautomer of Formula (III) is Formula(IIIa):

All forms of the compounds are also embraced by the invention, such ascrystalline or non-crystalline forms of the compounds. Compositionscomprising a compound of the invention are also intended, such as acomposition of substantially pure compound, including a specificstereochemical form thereof, or a composition comprising mixtures ofcompounds of the invention in any ratio, including two or morestereochemical forms, such as in a racemic or non-racemic mixture.

The invention also intends isotopically-labeled and/orisotopically-enriched forms of compounds described herein. The compoundsherein may contain unnatural proportions of atomic isotopes at one ormore of the atoms that constitute such compounds. In some embodiments,the compound is isotopically-labeled, such as an isotopically-labeledcompound of the formula (I) or variations thereof described herein,where a fraction of one or more atoms are replaced by an isotope of thesame element. Exemplary isotopes that can be incorporated into compoundsof the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C ¹³N, ¹⁵O,¹⁷O, ³²P, ³⁵S, ¹⁸F, ³⁶Cl. Certain isotope labeled compounds (e.g. ³H and¹⁴C) are useful in compound or substrate tissue distribution study.Incorporation of heavier isotopes such as deuterium (²H) can affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life, or reduced dosagerequirements and, hence may be preferred in some instances.

Isotopically-labeled compounds of the present invention can generally beprepared by standard methods and techniques known to those skilled inthe art or by procedures similar to those described in the accompanyingExamples substituting appropriate isotopically-labeled reagents in placeof the corresponding non-labeled reagent.

The invention also includes any or all metabolites of any of thecompounds described. The metabolites may include any chemical speciesgenerated by a biotransformation of any of the compounds described, suchas intermediates and products of metabolism of the compound, such aswould be generated in vivo following administration to a human.

Articles of manufacture comprising a compound described herein, or asalt or solvate thereof, in a suitable container are provided. Thecontainer may be a vial, jar, ampoule, preloaded syringe, i.v. bag, andthe like.

Preferably, the compounds detailed herein are orally bioavailable.However, the compounds may also be formulated for parenteral (e.g.,intravenous) administration.

One or several compounds described herein can be used in the preparationof a medicament by combining the compound or compounds as an activeingredient with a pharmacologically acceptable carrier, which are knownin the art. Depending on the therapeutic form of the medication, thecarrier may be in various forms. In one variation, the manufacture of amedicament is for use in any of the methods disclosed herein, e.g., forthe treatment of cancer.

General Synthetic Methods

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter (such as the schemes provided in the Examples below). In thefollowing process descriptions, the symbols when used in the formulaedepicted are to be understood to represent those groups described abovein relation to the formulae herein.

Where it is desired to obtain a particular enantiomer of a compound,this may be accomplished from a corresponding mixture of enantiomersusing any suitable conventional procedure for separating or resolvingenantiomers. Thus, for example, diastereomeric derivatives may beproduced by reaction of a mixture of enantiomers, e.g., a racemate, andan appropriate chiral compound. The diastereomers may then be separatedby any convenient means, for example by crystallization and the desiredenantiomer recovered. In another resolution process, a racemate may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

Solvates and/or polymorphs of a compound provided herein or apharmaceutically acceptable salt thereof are also contemplated. Solvatescontain either stoichiometric or non-stoichiometric amounts of asolvent, and are often formed during the process of crystallization.Hydrates are formed when the solvent is water, or alcoholates are formedwhen the solvent is alcohol. Polymorphs include the different crystalpacking arrangements of the same elemental composition of a compound.Polymorphs usually have different X-ray diffraction patterns, infraredspectra, melting points, density, hardness, crystal shape, optical andelectrical properties, stability, and/or solubility. Various factorssuch as the recrystallization solvent, rate of crystallization, andstorage temperature may cause a single crystal form to dominate

In some embodiments, compounds of the formula (I) may be synthesizedaccording to Scheme 1, 2, 3, 4, or 5.

wherein A and B are as defined for formula (I), or any variation thereofdetailed herein. It is understood that modifications of Scheme 1 can bemade, such as further substitution of the structures depicted.Particular examples are provided in the Example section below.

wherein A and B are as defined for formula (I), or any variation thereofdetailed herein. It is understood that modifications of Scheme 2 can bemade, such as further substitution of the structures depicted.Particular examples are provided in the Example section below.

wherein A B and R³ are as defined for formula (I), or any variationthereof detailed herein. It is understood that modifications of Scheme 3can be made, such as further substitution of the structures depicted.Particular examples are provided in the Example section below.

wherein A, B, R² and R³ are as defined for formula (I), or any variationthereof detailed herein. It is understood that modifications of Scheme 4can be made, such as further substitution of the structures depicted.Particular examples are provided in the Example section below.

wherein A, B and R² are as defined for formula (I), or any variationthereof detailed herein. It is understood that modifications of Scheme 4can be made, such as further substitution of the structures depicted.Particular examples are provided in the Example section below. It isunderstood that General Synthetic Scheme 1, Scheme 2, Scheme 3, Scheme4, Scheme 5 and present synthetic routes involving steps clearlyfamiliar to those skilled in the art, wherein the substituents describedin compounds of formula (I) herein can be varied with a choice ofappropriate starting materials and reagents utilized in the stepspresented. Pharmaceutical Compositions and Formulations

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this disclosure. Thus, the present disclosure includespharmaceutical compositions comprising a compound as detailed herein ora pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. In one aspect, the pharmaceuticallyacceptable salt is an acid addition salt, such as a salt formed with aninorganic or organic acid. Pharmaceutical compositions may take a formsuitable for oral, buccal, parenteral, nasal, topical or rectaladministration or a form suitable for administration by inhalation.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form.

In one variation, the compounds herein are synthetic compounds preparedfor administration to an individual. In another variation, compositionsare provided containing a compound in substantially pure form. Inanother variation, the present disclosure embraces pharmaceuticalcompositions comprising a compound detailed herein and apharmaceutically acceptable carrier. In another variation, methods ofadministering a compound are provided. The purified forms,pharmaceutical compositions and methods of administering the compoundsare suitable for any compound or form thereof detailed herein.

A compound detailed herein or salt thereof may be formulated for anyavailable delivery route, including an oral, mucosal (e.g., nasal,sublingual, vaginal, buccal or rectal), parenteral (e.g., intramuscular,subcutaneous or intravenous), topical or transdermal delivery form. Acompound or salt thereof may be formulated with suitable carriers toprovide delivery forms that include, but are not limited to, tablets,caplets, capsules (such as hard gelatin capsules or soft elastic gelatincapsules), cachets, troches, lozenges, gums, dispersions, suppositories,ointments, cataplasms (poultices), pastes, powders, dressings, creams,solutions, patches, aerosols (e.g., nasal spray or inhalers), gels,suspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions or water-in-oil liquid emulsions), solutions andelixirs.

One or several compounds described herein or a salt thereof can be usedin the preparation of a formulation, such as a pharmaceuticalformulation, by combining the compound or compounds, or a salt thereof,as an active ingredient with a pharmaceutically acceptable carrier, suchas those mentioned above. Depending on the therapeutic form of thesystem (e.g., transdermal patch vs. oral tablet), the carrier may be invarious forms. In addition, pharmaceutical formulations may containpreservatives, solubilizers, stabilizers, re-wetting agents, emulgators,sweeteners, dyes, adjusters, and salts for the adjustment of osmoticpressure, buffers, coating agents or antioxidants. Formulationscomprising the compound may also contain other substances which havevaluable therapeutic properties. Pharmaceutical formulations may beprepared by known pharmaceutical methods. Suitable formulations can befound, e.g., in Remington's Pharmaceutical Sciences, Mack PublishingCompany, Philadelphia, Pa., 20^(th) ed. (2000), which is incorporatedherein by reference.

Compounds as described herein may be administered to individuals in aform of generally accepted oral compositions, such as tablets, coatedtablets, and gel capsules in a hard or in soft shell, emulsions orsuspensions. Examples of carriers, which may be used for the preparationof such compositions, are lactose, corn starch or its derivatives, talc,stearate or its salts, etc. Acceptable carriers for gel capsules withsoft shell are, for instance, plant oils, wax, fats, semisolid andliquid poly-ols, and so on. In addition, pharmaceutical formulations maycontain preservatives, solubilizers, stabilizers, re-wetting agents,emulgators, sweeteners, dyes, adjusters, and salts for the adjustment ofosmotic pressure, buffers, coating agents or antioxidants.

Any of the compounds described herein can be formulated in a tablet inany dosage form described, for example, a compound as described hereinor a pharmaceutically acceptable salt thereof can be formulated as a 10mg tablet.

Compositions comprising a compound provided herein are also described.In one variation, the composition comprises a compound or salt thereofand a pharmaceutically acceptable carrier or excipient. In anothervariation, a composition of substantially pure compound is provided.

Methods of Use

Compounds and compositions detailed herein, such as a pharmaceuticalcomposition containing a compound of any formula provided herein or asalt thereof and a pharmaceutically acceptable carrier or excipient, maybe used in methods of administration and treatment as provided herein.The compounds and compositions may also be used in in vitro methods,such as in vitro methods of administering a compound or composition tocells for screening purposes and/or for conducting quality controlassays.

Provided herein is a method of treating a disease in an individualcomprising administering an effective amount of a compound of formula(I) or any embodiment, variation or aspect thereof (collectively, acompound of formula (I) or the present compounds or the compoundsdetailed or described herein) or a pharmaceutically acceptable saltthereof, to the individual. In some embodiments, provided herein is amethod of treating a disease mediated by a G protein coupled receptorsignaling pathway in an individual comprising administering an effectiveamount of a compound of formula (I), or a pharmaceutically acceptablesalt thereof, to the individual. In some embodiments, the disease ismediated by a class A G protein coupled receptor. In some embodiments,the disease is mediated by a class B G protein coupled receptor. In someembodiments, the disease is mediated by a class C G protein coupledreceptor. In some embodiments, the G protein coupled receptor is apurinergic G protein receptor. In some embodiments, the G proteincoupled receptor is an adenosine receptor, such as any of the A₁,A_(2A), A_(2B), and A₃ receptors.

The present compounds or salts thereof are believed to be effective fortreating a variety of diseases and disorders. For example, in someembodiments, the present compositions may be used to treat aproliferative disease, such as cancer. In some embodiments the cancer isa solid tumor. In some embodiments the cancer is any of adult andpediatric oncology, myxoid and round cell carcinoma, locally advancedtumors, metastatic cancer, human soft tissue sarcomas, including Ewing'ssarcoma, cancer metastases, including lymphatic metastases, squamouscell carcinoma, particularly of the head and neck, esophageal squamouscell carcinoma, oral carcinoma, blood cell malignancies, includingmultiple myeloma, leukemias, including acute lymphocytic leukemia, acutenonlymphocytic leukemia, chronic lymphocytic leukemia, chronicmyelocytic leukemia, and hairy cell leukemia, effusion lymphomas (bodycavity based lymphomas), thymic lymphoma lung cancer, including smallcell carcinoma, cutaneous T cell lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, cancer of the adrenal cortex, ACTH-producingtumors, nonsmall cell cancers, breast cancer, including small cellcarcinoma and ductal carcinoma, gastrointestinal cancers, includingstomach cancer, colon cancer, colorectal cancer, polyps associated withcolorectal neoplasia, pancreatic cancer, liver cancer, urologicalcancers, including bladder cancer, including primary superficial bladdertumors, invasive transitional cell carcinoma of the bladder, andmuscle-invasive bladder cancer, prostate cancer, malignancies of thefemale genital tract, including ovarian carcinoma, primary peritonealepithelial neoplasms, cervical carcinoma, uterine endometrial cancers,vaginal cancer, cancer of the vulva, uterine cancer and solid tumors inthe ovarian follicle, malignancies of the male genital tract, includingtesticular cancer and penile cancer, kidney cancer, including renal cellcarcinoma, brain cancer, including intrinsic brain tumors,neuroblastoma, astrocytic brain tumors, gliomas, metastatic tumor cellinvasion in the central nervous system, bone cancers, including osteomasand osteosarcomas, skin cancers, including melanoma, tumor progressionof human skin keratinocytes, squamous cell cancer, thyroid cancer,retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleuraleffusion, mesothelioma, Wilms's tumors, gall bladder cancer,trophoblastic neoplasms, hemangiopericytoma, and Kaposi's sarcoma.

In some embodiments, the present compounds or salts thereof are used intreatment of tumors which produce high levels of ATP and/or adenosine.For example, in some embodiments the extracellular concentration ofadenosine is 10-20 times higher in the tumor compared to adjacenttissue. In some embodiments, the present compounds or salts thereof areused in treatment of tumors that express high levels of anectonucleotidase. In some embodiments, the ectonucleotidase is CD39. Insome embodiments, the ectonucleotidase is CD73.

Also provided herein is a method of enhancing an immune response in anindividual in need thereof comprising administering an effective amountof a compound of formula (I), or a pharmaceutically acceptable saltthereof, to the individual. Adenosine receptors are known to play animmunosuppressive role in cancer biology. High levels of adenosinepresent in the tumor microenvironment bind to adenosine receptors onimmune cells to provide an immunosuppressive microenvironment.Specifically, binding of adenosine to the A_(2A) receptor provides animmunosuppressive signal that inhibits T cell proliferation, cytokineproduction and cytotoxicity. The A_(2A) receptor signaling has beenimplicated in adenosine-mediated inhibition of NK cell cytotoxicity, NKTcell cytokine production and CD40L upregulation. Therefore, use of anA_(2A) receptor antagonist, such as those provided herein, may reversethe immunosuppressive effect of adenosine on immune cells. In someembodiments, the immune response is enhanced by a compound of formula(I) or a salt thereof enhancing activity of natural killer (NK) cells.In some embodiments, the present compounds or salts thereof increase NKcell-meditated cytotoxicity. In some embodiments, the immune response isenhanced by enhancing the activity of CD8⁺ T cells. In some embodiments,the present compounds or salts thereof cause an inflammatory response inthe tumor microenvironment.

The present disclosure further provides a method of increasing theactivity of a natural killer cell in an individual comprisingadministering an effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, to the individual. In some ofthese embodiments, the present compounds or salts thereof increase NKcell-meditated cytotoxicity. In some embodiments, a compound of formula(I) or a salt thereof increases the number of NK cells.

A compound of formula (I) or a salt thereof may be useful for modulatingthe activity of G protein receptor coupled signaling pathway proteins.In some embodiments, a compound of formula (I) or a salt thereofactivates a G protein receptor coupled signaling pathway protein (i.e.is an agonist of a G protein receptor). In some embodiments, a compoundof formula (I) or a salt thereof inhibits a G protein receptor coupledsignaling pathway protein (i.e., is a G protein receptor antagonist). Insome embodiments, a compound of formula (I) or a salt thereof is anadenosine receptor antagonist. In some embodiments, a compound offormula (I) or a salt thereof is an antagonist of any of the A₁, A_(2A),A_(2B), and A₃ receptors.

Accordingly, also provided herein is a method of modulating the activityof an A_(2A) receptor in an individual comprising administering aneffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof to an individual. In some embodiments a compoundof formula (I) or a salt thereof is an A_(2A) receptor antagonist. Insome embodiments, a compound of formula (I) or a salt thereof reducesA_(2A) receptor signaling by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In someembodiments, a compound of formula (I) or a salt thereof reduces A_(2A)receptor signaling by 40-99%, 50-99%, 60-99%, 70-99%, 80-99%, 90-99%, or95-99%. In some of these embodiments, a compound of formula (I) or asalt thereof binds to the A_(2A) receptor with an IC₅₀ of less than 1μM, less than 900 nM, less than 800 nM, less than 700 nM, less than 600nM, less than 500 nM, less than 400 nM, less than 300 nM, less than 200nM, less than 100 nM, less than 10 nM, less than 1 nM or less than 100pM. In some embodiments, [compound x] binds to the A_(2A) receptor withan IC₅₀ of 500 nM to 100 pM, 400 nM to 100 pM, 300 nM to 100 pM, 200 nMto 100 pM, or 100 nM to 100 pM.

Also provided herein is a method of modulating the activity of an A_(2B)receptor in an individual comprising administering an effective amountof a compound of formula (I), or a pharmaceutically acceptable saltthereof to an individual. In some embodiments a compound of formula (I)or a salt thereof is an A_(2B) receptor antagonist. In some embodiments,a compound of formula (I) or a salt thereof reduces A_(2B) receptorsignaling by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, acompound of formula (I) or a salt thereof reduces A_(2B) receptorsignaling by 40-99%, 50-99%, 60-99%, 70-99%, 80-99%, 90-99%, or 95-99%.In some of these embodiments, a compound of formula (I) or a saltthereof binds to the A_(2B) receptor with an IC₅₀ of less than 1 μM,less than 900 nM, less than 800 nM, less than 700 nM, less than 600 nM,less than 500 nM, less than 400 nM, less than 300 nM, less than 200 nM,less than 100 nM, less than 10 nM, less than 1 nM or less than 100 pM.In some embodiments, a compound of formula (I) or a salt thereof bindsto the A_(2B) receptor with an IC₅₀ of 500 nM to 100 pM, 400 nM to 100pM, 300 nM to 100 pM, 200 nM to 100 pM, or 100 nM to 100 pM.

Also provided herein is a method of modulating the activity of an A₃receptor in an individual comprising administering an effective amountof a compound of formula (I), or a pharmaceutically acceptable saltthereof to an individual. In some embodiments a compound of formula (I)or a salt thereof is an A₃ receptor antagonist. In some embodiments, acompound of formula (I) or a salt thereof reduces A₃ receptor signalingby at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99%. In some embodiments, a compound offormula (I) or a salt thereof reduces A₃ receptor signaling by 40-99%,50-99%, 60-99%, 70-99%, 80-99%, 90-99%, or 95-99%. In some of theseembodiments, a compound of formula (I) or a salt thereof binds to the A₃receptor with an IC₅₀ of less than 1 μM, less than 900 nM, less than 800nM, less than 700 nM, less than 600 nM, less than 500 nM, less than 400nM, less than 300 nM, less than 200 nM, less than 100 nM, less than 10nM, less than 1 nM or less than 100 pM. In some embodiments, a compoundof formula (I) or a salt thereof binds to the A₃ receptor with an IC₅₀of 500 nM to 100 pM, 400 nM to 100 pM, 300 nM to 100 pM, 200 nM to 100pM, or 100 nM to 100 pM.

In some embodiments, the present invention comprises a method ofinhibiting tumor metastasis in an individual in need thereof comprisingadministering a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, to the individual. In some embodiments, themetastasis is to the lung, liver, lymph node, bone, adrenal gland,brain, peritoneum, muscle, or vagina. In some embodiments, a compound offormula (I) or a salt thereof inhibits metastasis of melanoma cells. Insome embodiments, the present disclosure includes a method of delayingtumor metastasis comprising administering a compound of formula (I), ora pharmaceutically acceptable salt thereof, to the individual. In someof these embodiments, the time to metastatic is delayed by 1 month, 2months 3 months, 4 months, 5 months, 6 months, 12 months, or more, upontreatment with the compounds of the present invention.

In some embodiments, a compound of formula (I) or a salt thereof is usedto treat an individual having a proliferative disease, such as cancer asdescribed herein. In some embodiments, the individual is at risk ofdeveloping a proliferative disease, such as cancer. In some of theseembodiments, the individual is determined to be at risk of developingcancer based upon one or more risk factors. In some of theseembodiments, the risk factor is a family history and/or gene associatedwith cancer. In some embodiments, the individual has a cancer thatexpresses a high level of a nucleotide metabolizing enzyme. In someembodiments, the nucleotide metabolizing enzyme is a nucleotidase, suchas CD73 (ecto-5′-nucleotidase, Ecto5′NTase). In some of theseembodiments, the individual has a cancer that expresses a high level ofa nucleotidase, such as CD73. In any of these embodiments, thenucleotide metabolizing enzyme is an ecto-nucleotidase. In someembodiments, the ecto-nucleotidase degrades adenosine monophosphate. Insome embodiments, the nucleotide metabolizing enzyme is CD39(ecto-nucleoside triphosphate diphosphohydrolase 1, E-NTPDase1). In someof these embodiments, the individual has a cancer that expresses a highlevel of CD39. In some embodiments, the individual has a cancer thatexpresses a high level of an adenosine receptor, such as the A_(2A)receptor.

Combination Therapy

As provided herein, the presently disclosed compounds or a salt thereofmay activate the immune system by modulating the activity of a G proteincoupled receptor signaling pathway, for example acting as an A_(2A)receptor antagonist, which results in significant anti-tumor effects.Accordingly, the present compounds or a salt thereof may be used incombination with other anti-cancer agents to enhance tumorimmunotherapy. In some embodiments, provided herein is a method oftreating a disease mediated by a G protein coupled receptor signalingpathway in an individual comprising administering an effective amount ofa compound of formula (I), or a pharmaceutically acceptable saltthereof, and an additional therapeutic agent to the individual. In someembodiments, the disease mediated by a G protein coupled receptorsignaling pathway is a proliferative disease such as cancer.

In some embodiments, the additional therapeutic agent is a cancerimmunotherapy. In some embodiments, the additional therapeutic agent isan immunostimulatory agent. In some embodiments, the additionaltherapeutic agent targets a checkpoint protein. In some embodiments, theadditional therapeutic agent is effective to stimulate, enhance orimprove an immune response against a tumor.

In another aspect, provided herein is a combination therapy in which acompound of formula (I) is coadministered (which may be separately orsimultaneously) with one or more additional agents that are effective instimulating immune responses to thereby further enhance, stimulate orupregulate immune responses in a subject. For example, provided is amethod for stimulating an immune response in a subject comprisingadministering to the subject a compound of formula (I) or a salt thereofand one or more immunostimulatory antibodies, such as an anti-PD-1antibody, an anti-PD-L1 antibody and/or an anti-CTLA-4 antibody, suchthat an immune response is stimulated in the subject, for example toinhibit tumor growth. As another example, provided is a method forstimulating an immune response in a subject comprising administering tothe subject a compound of formula (I) or a salt thereof and one or moreimmunostimulatory antibodies or immunotherapy like Chimeric antigenreceptor (CAR) T-cell therapy; immunostimulatory antibodies, such as ananti-PD-1 antibody, an anti-PD-L1 antibody and/or an anti-CTLA-4antibody, such that an immune response is stimulated in the subject, forexample to inhibit tumor growth. In one embodiment, the subject isadministered a compound of formula (I) or a salt thereof and ananti-PD-1 antibody. In another embodiment, the subject is administered acompound of formula (I) or a salt thereof and an anti-PD-L1 antibody. Inyet another embodiment, the subject is administered a compound offormula (I) or a salt thereof and an anti-CTLA-4 antibody. In anotherembodiment, the immunostimulatory antibody (e.g., anti-PD-1, anti-PD-L1and/or anti-CTLA-4 antibody) is a human antibody. Alternatively, theimmunostimulatory antibody can be, for example, a chimeric or humanizedantibody (e.g., prepared from a mouse anti-PD-1, anti-PD-L1 and/oranti-CTLA-4 antibody). In another embodiment, the subject isadministered a compound of formula (I) or a salt thereof and CAR T-cells(genetically modified T cells).

In one embodiment, the present disclosure provides a method for treatinga proliferative disease (e.g., cancer), comprising administering acompound of formula (I) or a salt thereof and an anti-PD-1 antibody to asubject. In further embodiments, a compound of formula (I) or a saltthereof is administered at a subtherapeutic dose, the anti-PD-1 antibodyis administered at a subtherapeutic dose, or both are administered at asubtherapeutic dose. In another embodiment, the present disclosureprovides a method for altering an adverse event associated withtreatment of a hyperproliferative disease with an immunostimulatoryagent, comprising administering a compound of formula (I) or a saltthereof and a subtherapeutic dose of anti-PD-1 antibody to a subject. Incertain embodiments, the subject is human. In certain embodiments, theanti-PD-1 antibody is a human sequence monoclonal antibody

In one embodiment, the present invention provides a method for treatinga hyperproliferative disease (e.g., cancer), comprising administering acompound of formula (I) or a salt thereof and an anti-PD-L1 antibody toa subject. In further embodiments, a compound of formula (I) or a saltthereof is administered at a subtherapeutic dose, the anti-PD-L1antibody is administered at a subtherapeutic dose, or both areadministered at a subtherapeutic dose. In another embodiment, thepresent invention provides a method for altering an adverse eventassociated with treatment of a hyperproliferative disease with animmunostimulatory agent, comprising administering a compound of formula(I) or a salt thereof and a subtherapeutic dose of anti-PD-L1 antibodyto a subject. In certain embodiments, the subject is human. In certainembodiments, the anti-PD-L1 antibody is a human sequence monoclonalantibody.

In certain embodiments, the combination of therapeutic agents discussedherein can be administered concurrently as a single composition in apharmaceutically acceptable carrier, or concurrently as separatecompositions each in a pharmaceutically acceptable carrier. In anotherembodiment, the combination of therapeutic agents can be administeredsequentially. For example, an anti-CTLA-4 antibody and a compound offormula (I) or a salt thereof can be administered sequentially, such asanti-CTLA-4 antibody being administered first and a compound of formula(I) or a salt thereof second, or a compound of formula (I) or a saltthereof being administered first and anti-CTLA-4 antibody second.Additionally or alternatively, an anti-PD-1 antibody and a compound offormula (I) or a salt thereof can be administered sequentially, such asanti-PD-1 antibody being administered first and a compound of formula(I) or a salt thereof second, or a compound of formula (I) or a saltthereof being administered first and anti-PD-1 antibody second.Additionally or alternatively, an anti-PD-L1 antibody and a compound offormula (I) or a salt thereof can be administered sequentially, such asanti-PD-L1 antibody being administered first and a compound of formula(I) or a salt thereof second, or a compound of formula (I) or a saltthereof being administered first and anti-PD-L1 antibody second.

Furthermore, if more than one dose of the combination therapy isadministered sequentially, the order of the sequential administrationcan be reversed or kept in the same order at each time point ofadministration, sequential administrations can be combined withconcurrent administrations, or any combination thereof.

Optionally, the combination of a compound of formula (I) or a saltthereof can be further combined with an immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.

A compound of formula (I) or a salt thereof can also be further combinedwith standard cancer treatments. For example, a compound of formula (I)or a salt thereof can be effectively combined with chemotherapeuticregimes. In these instances, it is possible to reduce the dose of otherchemotherapeutic reagent administered with the combination of theinstant disclosure (Mokyr et al. (1998) Cancer Research 58: 5301-5304).Other combination therapies with a compound of formula (I) or a saltthereof include radiation, surgery, or hormone deprivation. Angiogenesisinhibitors can also be combined with a compound of formula (I) or a saltthereof. Inhibition of angiogenesis leads to tumor cell death, which canbe a source of tumor antigen fed into host antigen presentationpathways.

In another example, a compound of formula (I) or a salt thereof can beused in conjunction with anti-neoplastic antibodies. By way of exampleand not wishing to be bound by theory, treatment with an anti-cancerantibody or an anti-cancer antibody conjugated to a toxin can lead tocancer cell death (e.g., tumor cells) which would potentiate an immuneresponse mediated by CTLA-4, PD-1, PD-L1 or a compound of formula (I) ora salt thereof. In an exemplary embodiment, a treatment of ahyperproliferative disease (e.g., a cancer tumor) can include ananti-cancer antibody in combination with a compound of formula (I) or asalt thereof and anti-CTLA-4 and/or anti-PD-1 and/or anti-PD-L1antibodies, concurrently or sequentially or any combination thereof,which can potentiate anti-tumor immune responses by the host. Otherantibodies that can be used to activate host immune responsiveness canbe further used in combination with a compound of formula (I) or a saltthereof.

In some embodiments, a compound of formula (I) or a salt thereof can becombined with an anti-CD73 therapy, such as an anti-CD73 antibody.

In some embodiments, a compound of formula (I) or a salt thereof can becombined with an anti-CD39 therapy, such as an anti-CD39 antibody.

In yet further embodiments, a compound of formula (I) or a salt thereofis administered in combination another G protein receptor antagonist,such as an adenosine A₁ and/or A₃ antagonist.

Dosing and Method of Administration

The dose of a compound administered to an individual (such as a human)may vary with the particular compound or salt thereof, the method ofadministration, and the particular disease, such as type and stage ofcancer, being treated. In some embodiments, the amount of the compoundor salt thereof is a therapeutically effective amount.

The effective amount of the compound may in one aspect be a dose ofbetween about 0.01 and about 100 mg/kg. Effective amounts or doses ofthe compounds of the invention may be ascertained by routine methods,such as modeling, dose escalation, or clinical trials, taking intoaccount routine factors, e.g., the mode or route of administration ordrug delivery, the pharmacokinetics of the agent, the severity andcourse of the disease to be treated, the subject's health status,condition, and weight. An exemplary dose is in the range of about fromabout 0.7 mg to 7 g daily, or about 7 mg to 350 mg daily, or about 350mg to 1.75 g daily, or about 1.75 to 7 g daily.

Any of the methods provided herein may in one aspect compriseadministering to an individual a pharmaceutical composition thatcontains an effective amount of a compound provided herein or a saltthereof and a pharmaceutically acceptable excipient.

A compound or composition of the invention may be administered to anindividual in accordance with an effective dosing regimen for a desiredperiod of time or duration, such as at least about one month, at leastabout 2 months, at least about 3 months, at least about 6 months, or atleast about 12 months or longer, which in some variations may be for theduration of the individual's life. In one variation, the compound isadministered on a daily or intermittent schedule. The compound can beadministered to an individual continuously (for example, at least oncedaily) over a period of time. The dosing frequency can also be less thanonce daily, e.g., about a once weekly dosing. The dosing frequency canbe more than once daily, e.g., twice or three times daily. The dosingfrequency can also be intermittent, including a ‘drug holiday’ (e.g.,once daily dosing for 7 days followed by no doses for 7 days, repeatedfor any 14 day time period, such as about 2 months, about 4 months,about 6 months or more). Any of the dosing frequencies can employ any ofthe compounds described herein together with any of the dosagesdescribed herein.

The compounds provided herein or a salt thereof may be administered toan individual via various routes, including, e.g., intravenous,intramuscular, subcutaneous, oral and transdermal. A compound providedherein can be administered frequently at low doses, known as ‘metronomictherapy,’ or as part of a maintenance therapy using compound alone or incombination with one or more additional drugs. Metronomic therapy ormaintenance therapy can comprise administration of a compound providedherein in cycles. Metronomic therapy or maintenance therapy can compriseintra-tumoral administration of a compound provided herein.

In one aspect, the invention provides a method of treating cancer in anindividual by parenterally administering to the individual (e.g., ahuman) an effective amount of a compound or salt thereof. In someembodiments, the route of administration is intravenous, intra-arterial,intramuscular, or subcutaneous. In some embodiments, the route ofadministration is oral. In still other embodiments, the route ofadministration is transdermal.

The invention also provides compositions (including pharmaceuticalcompositions) as described herein for the use in treating, preventing,and/or delaying the onset and/or development of cancer and other methodsdescribed herein. In certain embodiments, the composition comprises apharmaceutical formulation which is present in a unit dosage form.

Also provided are articles of manufacture comprising a compound of thedisclosure or a salt thereof, composition, and unit dosages describedherein in suitable packaging for use in the methods described herein.Suitable packaging is known in the art and includes, for example, vials,vessels, ampules, bottles, jars, flexible packaging and the like. Anarticle of manufacture may further be sterilized and/or sealed.

Kits

The present disclosure further provides kits for carrying out themethods of the invention, which comprises one or more compoundsdescribed herein or a composition comprising a compound describedherein. The kits may employ any of the compounds disclosed herein. Inone variation, the kit employs a compound described herein or apharmaceutically acceptable salt thereof. The kits may be used for anyone or more of the uses described herein, and, accordingly, may containinstructions for the treatment of cancer.

Kits generally comprise suitable packaging. The kits may comprise one ormore containers comprising any compound described herein. Each component(if there is more than one component) can be packaged in separatecontainers or some components can be combined in one container wherecross-reactivity and shelf life permit.

The kits may be in unit dosage forms, bulk packages (e.g., multi-dosepackages) or sub-unit doses. For example, kits may be provided thatcontain sufficient dosages of a compound as disclosed herein and/or asecond pharmaceutically active compound useful for a disease detailedherein (e.g., hypertension) to provide effective treatment of anindividual for an extended period, such as any of a week, 2 weeks, 3weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7months, 8 months, 9 months, or more. Kits may also include multiple unitdoses of the compounds and instructions for use and be packaged inquantities sufficient for storage and use in pharmacies (e.g., hospitalpharmacies and compounding pharmacies).

The kits may optionally include a set of instructions, generally writteninstructions, although electronic storage media (e.g., magnetic disketteor optical disk) containing instructions are also acceptable, relatingto the use of component(s) of the methods of the present invention. Theinstructions included with the kit generally include information as tothe components and their administration to an individual.

The invention can be further understood by reference to the followingexamples, which are provided by way of illustration and are not meant tobe limiting.

EXAMPLES Synthetic Examples Example S1. Synthesis of6-(3-chloro-4-hydroxy-phenyl)-7-phenyl-1H-1,8-naphthyridin-2-one(Compound No. 1.1)

Step 1: Synthesis of (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one

A mixture of DMF.DMA (21.9 g, 300 mmol, 3.6 equiv) and acetophenone(10.0 g, 1.0 equiv, 83 mmol) was heated at 100° C. for 16 h. Thereaction mixture was then cooled to RT and diluted with cold water. Theyellow precipitates were filtered under vacuum and washed with excesswater followed by hexane. The yellow solid (6 g) was used as such fornext step without further purification. LCMS: 176 [M+1]⁺

Step 2: Synthesis of ethyl 2-cyanoacetimidate

To a solution of malononitrile (10 g, 151.52 mmol) in diethyl ether (60mL) was cooled to 0° C. To this reaction mixture was ethanol (7.0 g,151.52 mmol, 1 equiv) added 2M HCl in diethyl ether (40 mL) and thereaction mixture was allowed to stir at 10° C. for 16 h. Theprecipitates formed were filtered and the solid was washed with etherand dried to give the desired product (6 g, 36%).

Step 3: Synthesis of 2-amino-6-phenylnicotinonitrile

To a solution of (E)-3-(dimethylamino)-1-phenyl-prop-2-en-1-one (3.0 g,18.18 mmol) in ethanol (100 mL) was added ethyl 2-cyanoethanimidatehydrochloride (3.2 g, 1.2 equiv, 21.82 mmol) and ammonium acetate (14 g,181.8 mmol, 10 equiv) and the reaction mixture was allowed to stir at85° C. for 16 h. Progress of the reaction was monitored by ¹H NMR.Reaction mixture was cooled to RT, diluted with cold water (250 mL) andthe solid was filtered. The solid was washed with hexane and dried undervacuum to afford 2.9 g (78%) of desired product.

LCMS: 196 [M+1]⁺

Step 4: Synthesis of 2-amino-5-bromo-6-phenylnicotinonitrile

To a stirred solution of 2-amino-6-phenyl-pyridine-3-carbonitrile (2.80g, 14.36 mmol, 1.0 equiv) in DMF (40 mL) was added NBS portion wise(2.56 g, 14.36 mmol, 1.0 equiv). The resulting solution was poured overice to get the precipitates which were filtered under vacuum, washedwith excess water and vacuum dried to get the desired product (3 g)which was used as such for next step without further purification.

LCMS: 274 [M+1]⁺

Step 5: Synthesis of 2-amino-5-bromo-6-phenylnicotinaldehyde

To a stirred solution of2-amino-5-bromo-6-phenyl-pyridine-3-carbonitrile (1.0 g, 3.64 mmol, 1.0equiv) in THF (30 mL) was added 1M solution of DIBAL-H in toluene (12.7mL, 12.7 mmol, 3.5 eq) and the reaction mixture was allowed to stir at0° C. for 45 min. Progress of the reaction was monitored by TLC and ¹HNMR. To the reaction mixture was added 2M HCl in water (16 mL) dropwiseat 0° C. and the reaction mixture was allowed to stir at the sametemperature for 10 min. The reaction mixture was basified with saturatedsodium carbonate solution (20 mL) and extracted with ethyl acetate (3×75mL). Combined organic layers were washed (brine), dried (anhydrousNa₂SO₄) and concentrated under vacuum to get the yellow solid (0.98 g)which was used as such for next step without further purification.

LCMS: 277 [M+1]⁺

Step 6: Synthesis of ethyl(E)-3-(2-amino-5-bromo-6-phenylpyridin-3-yl)acrylate

To a solution of ethyl 2-diethoxyphosphorylacetate (0.98 g, 4.38 mmol,1.0 equiv) in THF was added NaH (0.174 g, 4.38 mmol, 1.1 equiv) at 0° C.To this mixture was added2-amino-5-bromo-6-phenyl-pyridine-3-carbaldehyde (1.10 g, 3.97 mmol, 1.0equiv). Progress of the reaction was monitored by TLC. The reactionmixture was quenched by adding cold water and extracted by using ethylacetate. The combined organic layers were washed (brine), dried(anhydrous Na₂SO₄) and concentrated under vacuum to get the desiredproduct as yellow solid (0.210 g) which was used as such for next stepwithout further purification.

LCMS: 347 [M+1]⁺

Step 7 Synthesis of 6-bromo-7-phenyl-1,8-naphthyridin-2(1H)-one

Sodium metal (0.106 g, 4.0 equiv, 4.6 mmol) was added to ethanol (2 mL)at 0° C. The resulting mixture was stirred at this temperature for 15min. Solution of (E)-3-(2-amino-5-bromo-6-phenyl-3-pyridyl)prop-2-enoate(0.400 g, 1.15 mmol, 1.0 equiv) in ethanol (3 mL) was added to the abovereaction mixture at 0° C. and the resulting reaction mixture was heatedat 80° C. for 16 h. The reaction mixture was cooled to RT andneutralized by adding dilute HCl. The resulting precipitates werefiltered, washed with excess water followed by washing with hexane andvacuum dried to get the desired product which was purified by normalphase silica gel flash chromatography to get the desired product (0.300g).

LCMS: 301 [M+1]⁺

Step 8: Synthesis of6-(3-chloro-4-hydroxyphenyl)-7-phenyl-1,8-naphthyridin-2(1H)-one

To a stirred solution of 6-bromo-7-phenyl-1H-1,8-naphthyridin-2-one(0.140 g, 0.46 mmol, 1.0 eq) and (4-chloro-3-hydroxy-phenyl)boronic acid(0.104 g, 0.60 mmol, 1.3 eq) in dioxane (3 mL) was added 2M aq. Na₂CO₃(0.107 g, 1.0 mmol, 2.2 eq, 0.5 mL). The reaction was purged with N₂ for5 min. Following this Pd(dppf)Cl₂.DCM (0.018 g, 5 mol %) was added andN₂ was purged again for 5 minute. The reaction was then heated at 100°C. for 2 h. The reaction was allowed to cool to RT and extracted usingethyl acetate (2×30 mL). The combined organic layers were washed(brine), dried (anhydrous Na₂SO₄) and concentrated under vacuum to getthe solid which was purified by supercritical fluid chromatography toget the desired product (0.020 g, 16%).

LCMS: 349 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.21 (br. s., 1H), 10.26 (s, 1H), 8.16 (s,1H), 7.98 (d, J=9.78 Hz, 1H), 7.33 (s, 5H), 7.19 (s, 1H), 6.86 (q,J=8.64 Hz, 2H), 6.60 (d, J=10.27 Hz, 1H).

Example S2. Synthesis of6-(3-chloro-4-hydroxy-phenyl)-7-phenyl-1H-1,8-naphthyridin-4-one(Compound No. 1.2)

Step 1: Synthesis of 1-(2-amino-5-bromo-6-phenyl-3-pyridyl)ethanone

To a stirred solution of2-amino-5-bromo-6-phenyl-pyridine-3-carbonitrile (2.0 g, 7.30 mmol, 1.0eq) in THF (60 mL) was added 3M MeMgBr in diethyl ether (11.0 g, 146.9mmol, 20.0 equiv) at 0° C. The resulting reaction mixture was stirred at50° C. for 16 h. Reaction mixture was then cooled to 0° C. and quenchedby adding dilute HCl. The acidic reaction mixture was neutralized byusing aq. sodium bicarbonate solution and extracted by using ethylacetate (2×75 mL). The combined organic layers were washed (brine),dried (anhydrous Na₂SO₄) and concentrated under vacuum to get the lightgreen solid (2.0 g, 94%) which was used as such for next step withoutfurther purification

LCMS: 291 [M+1]⁺

Step 2: Synthesis of 6-bromo-7-phenyl-1H-1,8-naphthyridin-4-one

To a solution of 1-(2-amino-5-bromo-6-phenyl-3-pyridyl)ethanone (2.0 g,6.89 mmol, 1.0 eq) in DMF (10 mL) was added DMF-DMA (1.5 g, 20.68 mmol,3.0 equiv). The reaction mixture was warmed to 100° C. After stirringfor 3 h, Cs₂CO₃ (4.5 g, 13.78 mmol, 2.0 equiv) was added and thereaction was stirred for 16 h at 100° C. The reaction mixture was cooledto 0° C. and diluted with cold water. The resulting precipitates werefiltered, washed with excess water and vacuum dried. The solid obtainedwas purified by normal phase silica gel flash chromatography to get theyellow solid (0.250 g, 12%)

LCMS: 301 [M+1]⁺

Step 3: Synthesis of6-(3-chloro-4-hydroxy-phenyl)-7-phenyl-1H-1,8-naphthyridin-4-one

To a stirred solution of 6-bromo-7-phenyl-1H-1,8-naphthyridin-4-one(0.120 g, 0.40 mmol, 1.0 eq) and2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.127 g,0.50 mmol, 1.25 eq) in dioxane (5 mL) was added 0.4 mL 2M aq. Na₂CO₃(0.084 g, 0.8 mmol, 2.0 eq) under N₂. The reaction was purged with N₂for 5 min. Following this Pd(dppf)Cl₂.DCM (0.016 g, 5 mol %) was addedand N₂ was purged again for another 5 min. The reaction was then heatedat 100° C. for 4 h. The reaction was allowed to cool to RT and extractedusing ethyl acetate (2×30 mL). The combined organic layers were washed(brine), dried (anhydrous Na₂SO₄) and concentrated under vacuum to getthe solid which was purified by supercritical fluid chromatography toget the desired product (0.017 g, 12%).

LCMS: 349 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.39 (br. s., 1H), 10.30 (br. s., 1H), 8.32(s, 1H), 7.99 (br. s., 1H), 7.37 (d, J=2.93 Hz, 5H), 7.18 (d, J=1.96 Hz,1H), 6.92-7.00 (m, 1H), 6.88 (d, J=8.31 Hz, 1H), 6.16 (d, J=7.34 Hz,1H).

Example S3. Synthesis of6-(2,6-dimethylpyridin-4-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one(Compound No. 1.3)

To a stirred solution of (2,6-dimethylpyridin-4-yl)boronic acid (0.73 g,0.48 mmol, 1.2 equiv) and 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one(0.073 g, 0.40 mmol, 1.0 equiv) in dioxane (2 mL) was added Na₂CO₃(0.085 g, 0.80 mmol, 2.0 equiv) and water 0.8 mL. The reaction waspurged with N₂ for 5 min. To this reaction mixture was addedPd(dppf)Cl₂.DCM (0.016 g, 5 mol %) and N₂ was re-purged for another 5min. The reaction mixture was heated at 90° C. for 4 h. The reactionmixture was allowed to cool to RT and extracted using ethyl acetate(2×35 mL). The combined organic layers were washed (brine), dried(anhydrous Na₂SO₄) and concentrated under vacuum to get the solidresidue which was purified by reverse phase column chromatography to getthe desired product as off white solid (0.030 g, 22%).

LCMS: 328 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.37 (d, J=5.38 Hz, 1H), 8.39 (s, 1H),7.93-8.05 (m, 1H), 7.27-7.47 (m, 5H), 6.89 (s, 2H), 6.15 (d, J=7.34 Hz,1H), 2.33 (s, 6H).

Example S4. Synthesis of7-phenyl-6-(quinolin-6-yl)-1,8-naphthyridin-2(1H)-one (Compound No. 1.4)

To a stirred solution of quinolin-6-ylboronic acid (0.83 g, 0.48 mmol,1.2 equiv) and 6-bromo-7-phenyl-1,8-naphthyridin-2(1H)-one (0.120 g,0.40 mmol, 1.0 equiv) in dioxane (4 mL) was added 2M aqueous Na₂CO₃(0.084 g, 0.80 mmol, 2.0 equiv, 0.4 mL). The reaction was purged with N₂for 5 min. To this reaction mixture was added Pd(dppf)Cl₂.DCM (0.016 g,5 mol %) and N₂ was purged again for another 5 min. The reaction mixturewas heated at 90° C. for 4 h. The reaction mixture was allowed to coolto RT and extracted using ethyl acetate (2×35 mL). The combined organiclayers were washed (brine), dried (anhydrous Na₂SO₄) and concentratedunder vacuum to get the solid residue which was purified by reversephase column chromatography to get the desired product as off whitesolid (0.020 g, 14%).

LCMS: 350 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆): δ 12.32 (br. s., 1H), 9.01 (d, J=2.93 Hz,1H), 8.54 (d, J=7.83 Hz, 1H), 7.99-8.18 (m, 2H), 7.93 (d, J=8.80 Hz,1H), 7.70 (dd, J=4.65, 8.07 Hz, 1H), 7.52 (dd, J=1.47, 8.80 Hz, 1H),7.17-7.41 (m, 5H), 6.65 (d, J=9.78 Hz, 1H).

Example S5. Synthesis of7-phenyl-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one (Compound No. 1.5)

To a solution of 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one (100 mg,0.33 mmol, 1 eq.) in 1,4 dioxane (8 mL): water (2 mL) was addedquinolin-6-ylboronic acid (68 mg, 0.39 mmol, 1.1 eq.), Na₂CO₃ (70 mg,0.66 mmol, 2 eq.), PdCl₂(dppf).DCM complex (6 mg, 0.008 mmol, 0.025eq.). The reaction mixture was deoxygenated using N₂ atmosphere and thereaction mixture was heated at 80° C. for 18 h. The reaction wasmonitored by ¹H NMR and LCMS. The reaction mixture was diluted withwater (50 mL) and extracted using ethyl acetate (2×50 mL). The separatedorganic layer was dried over sodium sulfate and concentrated underreduced pressure. The crude product was purified by reverse phase columnchromatography to afford (8 mg, 8%) as desired product (8 mg, 8%).

LCMS: 350 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 6.18 (d, 1H), 7.30-7.40 (m, 3H), 7.40 (d,3H), 7.58 (m, 1H), 7.82 (d, 1H), 8.00 (d, 1H), 8.02 (s, 1H), 8.48 (d,1H), 8.50 (s, 1H), 8.90 (s, 1H).

Example S6. Synthesis of6-(1H-benzo[d]imidazol-5-yl)-7-phenyl-1,8-naphthyridin-2(1H)-one(Compound No. 1.6)

To a stirred solution of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole(0.117 g, 0.48 mmol, 1.2 equiv) and6-bromo-7-phenyl-1,8-naphthyridin-2(1H)-one (0.120 g, 0.40 mmol, 1.0equiv) in dioxane (3 mL) was added Na₂CO₃ (0.085 g, 0.80 mmol, 2.0equiv) and 1 mL water. The reaction was purged with N₂ for 5 min. Tothis reaction mixture was added Pd(dppf)Cl₂.DCM complex (0.017 g, 5 mol%) and N₂ was purged again for 5 more min. The reaction mixture washeated at 90° C. for 18 h. The reaction mixture was allowed to cool toRT and extracted using ethyl acetate (2×35 mL). The combined organiclayers were washed (brine), dried (anhydrous Na₂SO₄) and concentratedunder vacuum to get the solid residue which was purified by reversephase column chromatography to get the desired product as off whitesolid (0.015 g, 9%).

LCMS: 339 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ ¹H NMR (400 MHz, DMSO-d₆) 8.14-8.26 (m, 2H),8.01 (d, J=9.21 Hz, 1H), 7.46 (br. s., 2H), 7.34 (d, J=7.45 Hz, 2H),7.17-7.30 (m, 3H), 6.97 (d, J=7.89 Hz, 1H), 6.61 (d, J=9.21 Hz, 1H)

Example S7. Synthesis of6-(1H-benzo[d]imidazol-5-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one(Compound No. 1.7)

To a stirred solution of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole(0.117 g, 0.48 mmol, 1.2 equiv) and6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one (0.120 g, 0.40 mmol, 1.0equiv) in dioxane (3 mL) was added Na₂CO₃ (0.085 g, 0.80 mmol, 2.0equiv) and 1 mL water. The reaction was purged with N₂ for 5 min. Tothis reaction mixture was added Pd(dppf)Cl₂.DCM complex (0.017 g, 5 mol%) and N₂ was purged again for another 5 min. The reaction mixture washeated at 90° C. for 18 h. The reaction mixture was allowed to cool toRT and extracted using ethyl acetate (2×35 mL). The combined organiclayers were washed (brine), dried (anhydrous Na₂SO₄) and concentratedunder vacuum to get the solid residue which was purified by reversephase column chromatography to get the desired product as off whitesolid (0.010 g, 6%).

LCMS: 339 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.47 (br. s., 1H), 12.28 (br. s., 1H), 8.38(s, 1H), 8.21 (s, 1H), 7.98 (d, J=7.45 Hz, 1H), 7.46 (br. s., 2H), 7.38(d, J=7.02 Hz, 2H), 7.19-7.34 (m, 3H), 7.02 (br. s., 1H), 6.13 (d,J=7.45 Hz, 1H)

Example S8. Synthesis of1-methyl-7-phenyl-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one (CompoundNo. 1.8)

Step 1: Synthesis of6-bromo-1-methyl-7-phenyl-1,8-naphthyridin-4(1H)-one

To a solution of 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one (150 mg,0.5 mmol, 1.00 eq.) in DMF (3 mL) was added NaH (30 mg, 0.75 mmol, 1.5eq) at 0° C. After 10 min methyl iodide (85 mg, 0.6 mmol, 1.2 eq) wasadded at same temperature, The reaction mixture was stirred at roomtemperature for 18 h. The reaction mixture was diluted with ice coldwater (20 mL) and extracted with ethyl acetate (2×20 ml). The combinedorganic layer was wash with water (5×20 mL). The organic layer was driedover sodium sulfate and concentrated under reduced pressure to affordthe desired product (140 mg, 87%).

LCMS: 316 [M+1]⁺

Step 2: Synthesis of1-methyl-7-phenyl-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one

To a solution of 6-bromo-1-methyl-7-phenyl-1,8-naphthyridin-4(1H)-one(140 mg, 0.44 mmol, 1 eq.) in 1,4 dioxane (8 mL): water (2 mL) was addedquinolin-6-yl boronic acid (84 mg, 0.49 mmol, 1.1 eq.), Na₂CO₃ (94 mg,0.89 mmol, 2 eq.), and PdCl₂(dppf).DCM complex (18 mg, 0.022 mmol, 0.05eq). The reaction mixture was deoxygenated using N₂ atmosphere followedby heating at 80° C. for 48 h. The reaction was monitored by TLC andLCMS. The reaction mixture was diluted with water (30 mL) and extractedusing ethyl acetate (2×50 mL). The separated organic layer was driedover sodium sulfate and concentrated under reduced pressure. The crudeproduct was purified by reverse phase column chromatography to affordthe desired product (25 mg, 15%).

LCMS: 364 [M+1]⁺

¹H NMR (400 MHz, DMSO) δ 3.90 (s, 3H), 6.20 (d, 1H), 7.20-7.60 (m, 7H),7.82 (d, 1H), 8.03 (s, 1H) 8.20 (d, 1H), 8.38 (d, 1H), 8.58 (s, 1H),8.90 (d, 1H).

Example S9. Synthesis of6-(isoquinolin-6-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one (Compound No.1.9)

To a solution of 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one (100 mg,0.33 mmol, 1 eq.) in DME (8 mL): water (2 mL) was addedisoquinolin-6-ylboronic acid (63 mg, 0.36 mmol, 1.1 eq.), Na₂CO₃ (70 mg,0.66 mmol, 2 eq.), Pd(PPh₃)₄(11 mg, 0.011 mmol, 0.03 eq). The reactionmixture was deoxygenated using N₂ atmosphere and the reaction mixturewas heated at 130° C. for 1 h under microwave irradiation. The reactionwas monitored by NMR and LCMS. The reaction mixture was diluted withwater (30 mL) and extracted using ethyl acetate (2×50 mL). The separatedorganic layer was dried over sodium sulfate and concentrated underreduced pressure. The crude product was purified by reverse phase columnchromatography to afford the desired product as a TFA salt (8 mg, 11%).

LCMS: 350 [M+1]⁺

¹H NMR (400 MHz, DMSO) δ 6.20 (d, 1H), 7.30-7.42 (m, 5H), 7.50 (d, 1H),8.02 (d, 1H), 8.18 (d, H), 8.22 (s, 1H), 8.58 (s, 1H), 8.60 (d, 1H),9.50 (s, 1H), 12.42 (bs, 1H).

Example S10. Synthesis of7-phenyl-6-(quinoxalin-6-yl)-1,8-naphthyridin-2(1H)-one (Compound No.1.10)

To a stirred solution of quinoxalin-6-ylboronic acid (0.84 g, 0.48 mmol,1.2 equiv) and 6-bromo-7-phenyl-1,8-naphthyridin-2(1H)-one (0.120 g,0.40 mmol, 1.0 equiv) in dioxane (3 mL) was added Na₂CO₃ (0.085 g, 0.80mmol, 2.0 equiv) and 1 mL water. The reaction was purged with N₂ for 5min. To this reaction mixture was added Pd(dppf)Cl₂.DCM complex (0.017g, 5 mol %) and N₂ was purged again for 5 more min. The reaction mixturewas heated at 90° C. for 18 h. The reaction mixture was allowed to coolto RT and extracted using ethyl acetate (2×35 mL). The combined organiclayers were washed (brine), dried (anhydrous Na₂SO₄) and concentratedunder vacuum to get the solid residue which was purified by reversedphase column chromatography to get the desired product as off whitesolid (0.006 g, 4%).

LCMS: 351 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆)¹H NMR (400 MHz, DMSO-d₆) 8.84-8.93 (m, 2H),8.31 (s, 1H), 8.02-8.14 (m, 2H), 7.91-8.00 (m, 1H), 7.56-7.67 (m, 2H),7.44 (d, J=7.02 Hz, 2H), 7.17-7.34 (m, 3H), 6.73 (d, J=9.21 Hz, 1H).

Example S11. Synthesis of 2-phenyl-[3,3′-bi(1,8-naphthyridin)]-5(8H)-one(Compound No. 1.11)

Step 1: Synthesis of (1,8-naphthyridin-3-yl)boronic acid

To a solution of 3-bromo-1,8-naphthyridine (0.160 g, 0.76 mmol, 1 eq.)in 1,4-dioxane (3 mL) was added 5-(4,4,5,5-bis(pinacolato)diboron (0.289mg, 1.14 mmol, 1.5 eq.), KOAc (0.224 g, 2.28 mmol, 3 eq.), andPd(PPh₃)Cl₂ complex (0.026 g, 0.038 mmol, 0.05 eq.). The reactionmixture was deoxygenated with N₂ allowed stir at 80° C. for 16 h. Thereaction mixture was cooled to RT and filtered through Celite. Thefiltrate was concentrated (0.120 g, 90%) and used for next step withoutfurther purification.

LCMS: 175 [M+1]⁺

Step 2: Synthesis of 2-phenyl-[3,3′-bi(1,8-naphthyridin)]-5(8H)-one

To a stirred solution of (1,8-naphthyridin-3-yl)boronic acid (0.068 g,0.39 mmol, 1.2 equiv) and 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one(0.100 g, 0.33 mmol, 1.0 equiv) in dioxane (3 mL) was added Na₂CO₃(0.069 g, 0.66 mmol, 2.0 equiv) and 1 mL water. The reaction was purgedwith N₂ for 5 min. To this reaction mixture was added Pd(dppf)Cl₂.DCMcomplex (0.014 g, 5 mol %) and N₂ was purged again for another 5 min.The reaction mixture was heated at 90° C. for 18 h. The reaction mixturewas allowed to cool to RT and extracted using ethyl acetate (2×35 mL).The combined organic layers were washed (brine), dried (anhydrousNa₂SO₄) and concentrated under vacuum to get the solid residue which waspurified by reversed phase column chromatography to get the desiredproduct as off white solid (0.040 g, 29%).

LCMS: 351 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.52 (br. s., 1H), 9.14 (br. s., 1H), 8.70(d, J=5.26 Hz, 2H), 8.48-8.67 (m, 2H), 8.05 (d, J=7.45 Hz, 1H), 7.78 (d,J=3.95 Hz, 1H), 7.24-7.48 (m, 4H), 6.21 (d, J=7.89 Hz, 1H)

Example S12. Synthesis of6-(8-chloroquinolin-6-yl)-7-phenyl-1,8-naphthyridin-2 (1H)-one (CompoundNo. 1.12)

To a stirred solution of (8-chloroquinolin-6-yl)boronic acid (0.083 g,0.40 mmol, 1.2 equiv) and 6-bromo-7-phenyl-1,8-naphthyridin-2(1H)-one(0.100 g, 0.33 mmol, 1.0 equiv) in dioxane (3 mL) was added Na₂CO₃(0.070 g, 0.66 mmol, 2.0 equiv) and 1 mL water. The reaction was purgedwith N₂ for 5 min. To this reaction mixture was added Pd(dppf)Cl₂.DCMcomplex (0.014 g, 5 mol %) and N₂ was purged again for another 5 min.The reaction mixture was heated at 90° C. for 18 h. The reaction mixturewas allowed to cool to RT and extracted using ethyl acetate (2×35 mL).The combined organic layers were washed (brine), dried (anhydrousNa₂SO₄) and concentrated under vacuum to get the solid residue which waspurified by reversed phase column chromatography to get the desiredproduct as off white solid (0.013 g, 10%).

LCMS: 384 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ¹H NMR (400 MHz, DMSO-d₆) 12.34 (br. s., 1H),9.01 (d, J=3.07 Hz, 1H), 8.30-8.46 (m, 2H), 8.03 (d, J=9.21 Hz, 1H),7.94 (s, 1H), 7.57-7.73 (m, 2H), 7.23-7.45 (m, 5H), 6.66 (d, J=9.65 Hz,1H)

Example S13. Synthesis of6-(8-chloroquinolin-6-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one (CompoundNo. 1.13)

To a stirred solution of 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one(0.100 g, 0.33 mmol, 1.0 equiv) and (8-chloroquinolin-6-yl)boronic acid(0.083 g, 0.40 mmol, 1.2 equiv) in dioxane (3 mL) was added Na₂CO₃(0.070 g, 0.66 mmol, 2.0 equiv) and 1 mL water. The reaction was purgedwith N₂ for 5 min. To this reaction mixture was added Pd(dppf)Cl₂.DCMcomplex (0.014 g, 5 mol %) and N₂ was purged again for another 5 min.The reaction mixture was heated at 90° C. for 16 h. The reaction mixturewas allowed to cool to RT and extracted using ethyl acetate (2×35 mL).The combined organic layers were washed (brine), dried (anhydrousNa₂SO₄) and concentrated under vacuum to get the solid residue which waspurified by reversed phase column chromatography to get the desiredproduct as off white solid (0.010 g, 10%).

LCMS: 384 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (d, J=2.63 Hz, 1H), 8.55 (s, 1H), 8.43(d, J=7.02 Hz, 1H), 7.97-8.11 (m, 2H), 7.66 (dd, J=4.38, 8.33 Hz, 1H),7.59 (d, J=1.75 Hz, 1H), 7.28-7.45 (m, 5H), 6.18 (d, J=7.45 Hz, 1H)

Example S14. Synthesis of7-(furan-2-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one (CompoundNo. 1.14)

Step 1: Synthesis of 3-(dimethylamino)-1-(furan-2-yl)prop-2-en-1-one

A mixture of DMF.DMA (21.9 g, 297.17 mmol, 3.6 eq) and1-(furan-2-yl)ethanone (10.0 g, 90.81 mmol, 1.0 eq,) was heated at 100°C. for 16 h. The reaction mixture was then cooled to RT and diluted withcold water. The yellow precipitates were filtered under vacuum andwashed with excess water followed by hexane. The yellow solid (13.4 g,88%) was used as such for next step without further purification.

LCMS: 166 [M+1]⁺

Step 2: Synthesis of 2-amino-6-(furan-2-yl)nicotinonitrile

To a solution of 3-(dimethylamino)-1-(furan-2-yl)prop-2-en-1-one (9.0 g,54.54 mmol. 1.00 eq) in ethanol (200 mL) was added ethyl2-cyanoethanimidate hydrochloride (9.68 g, 1.2 eq, 65.45 mmol) andammonium acetate (48.50 g, 54.5 mmol, 10 eq). The reaction mixture wasallowed to stir at 85° C. for 16 h. Progress of the reaction wasmonitored by LCMS. Reaction mixture was cooled to RT, diluted with coldwater (250 mL) and the solid was filtered. The solid was washed withhexane and dried under vacuum to afford the desired product (5.7 g,57%).

LCMS: 186 [M+1]⁺

Step 3: Synthesis of 2-amino-5-bromo-6-(furan-2-yl)nicotinonitrile

To a stirred solution of 2-amino-6-(furan-2-yl)nicotinonitrile (3.0 g16.21 mmol, 1.0 equiv) in DMF (120 mL) was added NBS portion wise (2.88g, 16.21 mmol, 1.0 equiv). The reaction mixture was allowed to stir atRT. The progress of the reaction was monitored by TLC. After completionof the reaction the reaction mixture was poured over ice to get theprecipitates which were filtered under vacuum, washed with excess waterand vacuum dried to get the desired product (2.2 g, 52%) which was usedas such for next step without further purification.

LCMS: 264 [M+1]⁺

Step 4: Synthesis of1-(2-amino-5-bromo-6-(furan-2-yl)pyridin-3-yl)ethanone

To a stirred solution of 2-amino-5-bromo-6-(furan-2-yl)nicotinonitrile(1.6 g, 6.08 mmol, 1.0 eq) in THF (60 mL) was added 3M MeMgBr in diethylether (40.0 mL, 121.6 mmol, 20.0 equiv) at 0° C. The resulting reactionmixture was stirred at 50° C. for 16 h. Reaction mixture was then cooledto 0° C. and quenched by adding dilute HCl. The acidic reaction mixturewas neutralized by using aq. sodium bicarbonate solution and extractedby using ethyl acetate (2×75 mL). The combined organic layers werewashed (brine), dried (anhydrous Na₂SO₄) and concentrated under vacuumto get the light green solid (1.1 g, 64%). which was used as such fornext step without further purification

LCMS: 281 [M+1]⁺

Step 5: Synthesis of1-(2-amino-5-bromo-6-(furan-2-yl)pyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one

To a solution of 1-(2-amino-5-bromo-6-(furan-2-yl)pyridin-3-yl)ethanone(1.0 g, 3.58 mmol, 1.0 eq) in 1,4-dioxane (10 mL) was added DMF.DMA(0.52 mL 3.94 mmol, 1.1 equiv). The reaction mixture was warmed to 100°C. for 3 h. The reaction solvent was evaporated under reduced pressureto afford the desired product (800 mg, 61%).

LCMS: 336 [M+1]⁺

Step 6: Synthesis of 6-bromo-7-(furan-2-yl)-1,8-naphthyridin-4(1H)-one

To a stirred solution of1-(2-amino-5-bromo-6-(furan-2-yl)pyridin-3-yl)-3-(dimethylamino)prop-2-en-1-one(1.0 g, 2.98 mmol, 1.0 eq) in DMF (10.0 mL) was added Cs₂CO₃ (1.94 g,2.0 eq, 5.97 mmol) and allowed to stir at 100° C. for 16 h. Progress ofreaction was monitored by TLC. The reaction mixture was diluted with icecold water and the resulting precipitates were filtered and vacuum driedto get the desired product (0.400 g, 50%).

LCMS: 291[M+1]⁺

Step 7: Synthesis of7-(furan-2-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one

To a stirred solution of6-bromo-7-(furan-2-yl)-1,8-naphthyridin-4(1H)-one (0.100 g, 0.34 mmol,1.0 eq), quinoline (0.072 g, 0.41 mmol, 1.2 eq) in dioxane (5 mL) wasadded 0.4 mL 2M aq. Na₂CO₃ (0.073 g, 0.68 mmol, 2.0 eq) under N₂. Thereaction was purged with N₂ for 5 min. Following this Pd(dppf)Cl₂.DCM(0.014 g, 5 mol %) was added and N₂ was purged again for another 5 min.The reaction was then heated at 100° C. for 16 h. The reaction wasallowed to cool to RT and extracted using ethyl acetate (2×30 mL). Thecombined organic layers were washed (brine), dried (anhydrous Na₂SO₄)and concentrated under vacuum to get the solid which was purified bysupercritical fluid chromatography to get the desired product (0.018 g,15%).

LCMS: 340 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.42 (s, 1H), 8.98 (d, J=2.63 Hz, 1H), 8.46(d, J=8.77 Hz, 1H), 8.35 (s, 1H), 7.91-8.15 (m, 3H), 7.55-7.76 (m, 3H),6.44-6.54 (m, 1H), 6.31 (d, J=3.07 Hz, 1H), 6.14 (d, J=7.45 Hz, 1H).

Example S15. Synthesis of7-phenyl-6-(quinoxalin-6-yl)-1,8-naphthyridin-4(1H)-one (Compound No.1.15)

To a solution of 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one (100 mg,0.33 mmol, 1 eq.) in DME (8 mL): water (2 mL) was addedquinoxalin-6-ylboronic acid (63 mg, 0.36 mmol, 1.1 eq.), Na₂CO₃ (70 mg,0.66 mmol, 2 eq.), Pd(PPh₃)₄(11 mg, 0.008 mmol, 0.025 eq.). The reactionmixture was deoxygenated using N₂ atmosphere and the reaction mixturewas heated at 130° C. for 1 h under microwave irradiation. The reactionwas monitored by LCMS. The reaction mixture was diluted with water (20mL) and extracted using ethyl acetate (2×20 mL). The separated organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude product was purified by reverse phase columnchromatography to afford the desired product (15 mg, 13%).

LCMS: 351 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 6.20 (d, 1H), 7.30 (m, 3H), 7.40 (d, 2H),7.60 (d, 1H), 8.00 (m, 3H), 8.58 (s, 1H), 8.88 (s, 2H).

Example S16. Synthesis of6-(naphthalen-2-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one. (Compound No.1.16)

To a solution of 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one (100 mg,0.33 mmol, 1 eq.) in dioxane (8 mL): water (2 mL) was addednaphthalen-2-ylboronic acid (62 mg, 0.36 mmol, 1.1 eq.), Na₂CO₃ (70 mg,0.66 mmol, 2 eq.), Pd(PPh₃)₄(13 mg, 0.008 mmol, 0.05 eq.). The reactionmixture was deoxygenated using N₂ atmosphere and the reaction mixturewas heated at 100° C. for 18 h. The reaction was monitored by LCMS. Thereaction mixture was diluted with water (20 mL) and extracted usingethyl acetate (2×20 mL). The separated organic layer was dried overanhydrous sodium sulfate and concentrated under reduced pressure. Thecrude product was purified by reverse phase column chromatography toafford the desired product (12 mg, 9%).

LCMS: 349 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 6.18 (d, 1H), 7.18 (d, 1H), 7.30 (m, 3H),7.40 (d, 2H), 7.52 (d, 2H), 7.78 (d, 1H), 7.90 (t, 2H), 8.00 (m, 2H),8.50 (s, 1H).

Example S17. Synthesis of6-(7-chloro-1H-benzo[d]imidazol-5-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one(Compound No. 1.17)

To a stirred solution of 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one(0.100 g, 0.33 mmol, 1.0 equiv) and(7-chloro-1H-benzo[d]imidazol-5-yl)boronic acid (0.108 g, 0.39 mmol, 1.2equiv) in dioxane (3 mL) was added Na₂CO₃ (0.069 g, 0.66 mmol, 2.0equiv) and 1 mL water. The reaction was purged with N₂ for 5 min. Tothis reaction mixture was added Pd(dppf)Cl₂.DCM complex (0.014 g, 5 mol%) and N₂ was purged again for another 5 min. The reaction mixture washeated at 90° C. for 16 h. The reaction mixture was allowed to cool toRT and extracted using ethyl acetate (2×35 mL). The combined organiclayers were washed (brine), dried (anhydrous Na₂SO₄) and concentratedunder vacuum to get the solid residue which was purified by reversedphase column chromatography to get the desired product as off whitesolid (0.008 g, 7%).

LCMS: 373 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 8.40 (s, 1H), 8.30 (s, 1H), 8.00 (d, J=7.45Hz, 1H), 7.25-7.44 (m, 6H), 7.10 (br. s., 1H), 6.15 (d, J=7.89 Hz, 1H)

Example S18. Synthesis of7-(pyridin-4-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one (CompoundNo. 1.18)

Step 1: Synthesis of(E)-3-(dimethylamino)-1-(pyridin-4-yl)prop-2-en-1-one

A mixture of DMF-DMA (21.9 g, 297.17 mmol, 3.6 eq) and1-(pyridin-4-yl)ethan-1-one (10.0 g, 1.0 eq, 83 mmol) was heated at 100°C. for 16 h. The reaction mixture was then cooled to RT and diluted withcold water. The yellow precipitates were filtered under vacuum andwashed with excess water followed by hexane. The yellow solid (14.8 g)was used as such for next step without further purification.

LCMS: 176 [M+1]⁺

Step 2: Synthesis of 6-amino-[2,4′-bipyridine]-5-carbonitrile

To a solution of (E)-3-(dimethylamino)-1-phenyl-prop-2-en-1-one (11.0 g,62.5 mmol) in ethanol (200 mL) was added ethyl 2-cyanoethanimidatehydrochloride 11.1 g, 1.2 equiv, 75.0 mmol) and ammonium acetate (55.62g, 625.0 mmol, 10 equiv) and the reaction mixture was allowed to stir at85° C. for 16 h. Progress of the reaction was monitored by ¹H NMR.Reaction mixture was cooled to RT, diluted with cold water (250 mL) andthe solid was filtered. The solid was washed with hexane and dried undervacuum to afford the desired product (9.8 g, 80%)

LCMS: 196 [M+1]⁺

Step 3: Synthesis of 6-amino-3-bromo-[2,4′-bipyridine]-5-carbonitrile

To a stirred solution of 6-amino-[2,4′-bipyridine]-5-carbonitrile (11.0g, 56.06 mmol, 1.0 equiv) in DMF (120 mL) was added NBS portion wise(9.97 g, 56.06 mmol, 1.0 equiv). The resulting solution was poured overice to get the precipitates which were filtered under vacuum, washedwith excess water and vacuum dried to get the desired product (9.8 g,64%) which was used as such for next step without further purification.

LCMS: 275 [M+1]⁺

Step 4: Synthesis of1-(6-amino-3-bromo-[2,4′-bipyridin]-5-yl)ethan-1-one

To a stirred solution of6-amino-3-bromo-[2,4′-bipyridine]-5-carbonitrile (4.0 g, 14.59 mmol, 1.0eq) in THF (60 mL) was added 3M MeMgBr in diethyl ether (35.0 ml, 291.8mmol, 20.0 equiv) at 0° C. The resulting reaction mixture was stirred at50° C. for 16 h. Reaction mixture was then cooled to 0° C. and quenchedby adding dilute HCl. The acidic reaction mixture was neutralized byusing aq. sodium bicarbonate solution and extracted by using ethylacetate (2×75 mL). The combined organic layers were washed (brine),dried (anhydrous Na₂SO₄) and concentrated under vacuum to get the lightgreen solid (2.27 g, 51%) which was used as such for next step withoutfurther purification.

LCMS: 292 [M+1]⁺

Step 5: Synthesis of 6-bromo-7-(pyridin-4-yl)-1,8-naphthyridin-4(1H)-one

To a solution of 1-(6-amino-3-bromo-[2,4′-bipyridin]-5-yl)ethan-1-one(1.3 g, 4.46 mmol, 1.0 eq) in DMF (10 mL) was added DMF.DMA (1.06 g,8.92 mmol, 2.0 equiv). The reaction mixture was warmed to 100° C. Afterstirring for 3 h, Cs₂CO₃ (4.5 g, 13.78 mmol, 2.0 equiv) was added andthe reaction was stirred for 16 h at 100° C. The reaction mixture wascooled to 0° C. and diluted with cold water. The resulting precipitateswere filtered, washed with excess water and vacuum dried. The solidobtained was purified by normal phase silica gel flash chromatography toget the yellow solid (0.700 g, 54%).

LCMS: 302 [M+1]⁺

Step 6: Synthesis of7-(pyridin-4-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one

To a stirred solution of6-bromo-7-(pyridin-4-yl)-1,8-naphthyridin-4(1H)-one (0.100 g, 0.33 mmol,1.0 eq) and quinolin-6-ylboronic acid (0.068 g, 0.39 mmol, 1.2 eq) indioxane (5 mL) was added 0.4 mL 2M aq. Na₂CO₃ (0.070 g, 0.66 mmol, 2.0eq) under N₂. The reaction was purged with N₂ for 5 min. Following thisPd(dppf)Cl₂.DCM (0.014 g, 5 mol %) was added and N₂ was purged again foranother 5 min. The reaction was then heated at 100° C. for 16 h. Thereaction was allowed to cool to RT and extracted using ethyl acetate(2×30 mL). The combined organic layers were washed (brine), dried(anhydrous Na₂SO₄) and concentrated under vacuum to get the solid whichwas purified by supercritical fluid chromatography to get the desiredproduct (0.063 g, 54%).

LCMS: 351 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ ¹H NMR (400 MHz, DMSO-d₆ 7.3-7.4 (2H),7.4-7.5 (1H), 7.5-7.6 (1H), 7.8-7.9 (1H) 8.0-8.1 (2H), 8.3-8.4 (1H)8.5-8.6 (1H), 8.6-8.7 (1H), 8.9-9.0 (1H), 12.5-12.6 (1H).

Example S19. Synthesis of6-(7-chloro-1H-benzo[d]imidazol-5-yl)-7-phenyl-1,8-naphthyridin-2(1H)-one(Compound No. 1.19)

To a stirred solution of 6-bromo-7-phenyl-1,8-naphthyridin-2(1H)-one(0.100 g, 0.33 mmol, 1.0 equiv) and(7-chloro-1H-benzo[d]imidazol-5-yl)boronic acid (0.108 g, 0.39 mmol, 1.2equiv) in dioxane (3 mL) was added Na₂CO₃ (0.069 g, 0.66 mmol, 2.0equiv) and 1 mL water. The reaction was purged with N₂ for 5 min. Tothis reaction mixture was added Pd(dppf)Cl₂.DCM complex (0.014 g, 5 mol%) and N₂ was purged again for another 5 min. The reaction mixture washeated at 90° C. for 16 h. The reaction mixture was allowed to cool toRT and extracted using ethyl acetate (2×35 mL). The combined organiclayers were washed (brine), dried (anhydrous Na₂SO₄) and concentratedunder vacuum to get the solid residue which was purified by reversedphase column chromatography to get the desired product as off whitesolid (0.008 g, 7%).

LCMS: 373 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 12.25 (br. s., 1H), 8.25 (s, 1H), 8.29 (s,1H), 8.01 (d, J=9.65 Hz, 1H), 7.35 (d, J=7.45 Hz, 3H), 7.28 (d, J=7.02Hz, 3H), 7.10 (s, 1H), 6.62 (d, J=9.21 Hz, 1H)

Example S20. Synthesis of7-(pyridin-3-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one. (CompoundNo. 1.20)

Step 1: 1-(3-amino-5-phenyl-6-(quinolin-6-yl)pyrazin-2-yl)ethan-1-one

To a stirred solution of3-amino-5-phenyl-6-(quinolin-6-yl)pyrazine-2-carbonitrile (0.100 g, 0.32mmol, 1.0 eq) in THF (5 mL) was added 3M MeMgBr in diethyl ether (1 mL,0.360 g, 10.0 eq, 3.0 mmol) at 0° C. The resulting reaction mixture wasstirred at 50° C. for 16 h. Reaction mixture was then cool to RT andacidified slowly with dilute HCl. The acidified reaction mixture wasstirred for 1 h at 50° C. The reaction mixture was again allowed to coolto RT and extracted by using ethyl acetate (2×25 mL). The combinedorganic layers were washed (brine), dried (anhydrous Na₂SO₄) andconcentrated under vacuum to get the desired product as light yellowsolid (0.090 g, 97%)

LCMS: 291 [M+1]⁺

Step 2: Synthesis of7-(pyridin-3-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one

To a solution of1-(6-amino-3-(quinolin-6-yl)-2,3′-bipyridin-5-yl)ethanone (0.090 g, 0.31mmol, 1.00 eq.), in 1,4 dioxane (5 mL), was added DMF:DMA (0.044 g, 0.37mmol, 1.2 eq.). The reaction mixture was heated at 90° C. for 30 minute.The reaction was monitored by TLC and LCMS. The reaction solvent wasevaporated under reduced pressure. The semisolid crude material obtainedwas redissolved in DMF (2 mL) and Cs₂CO₃ (0.150 g, 0.46 mmol, 1.5 eq.)was added. The reaction mixture was again heated at 90° C. for 18 h. Theprogress of the reaction was monitored by LCMS. The reaction mixture wasdiluted with ice cold water (25 mL) and extracted by using ethyl acetate(3×25 mL). The residue was purified by reverse phase columnchromatography to afford the desired product (0.010 g, 10%).

LCMS: 351 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (d, J=3.07 Hz, 1H), 8.35 (d, J=7.45 Hz,1H), 8.14 (br. s., 1H), 8.06 (d, J=5.26 Hz, 1H), 7.91 (d, J=8.77 Hz,1H), 7.65 (d, J=7.02 Hz, 1H), 7.45-7.59 (m, 3H), 7.29-7.44 (m, 3H), 6.33(d, J=7.02 Hz, 1H)

Example S21. Synthesis of6-(benzo[d]oxazol-5-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one (CompoundNo. 1.21)

Step 1: Synthesis of 4-bromo-2-nitrophenol

To a solution of 6-bromophenol (5 g, 28.90 mmol, 1 eq.) in acetic acid(10 mL) was added nitric acid (1 mL) drop wise. Reaction mixture wasstirred at RT for 5 min. The reaction was monitored by LCMS and found tobe complete after 5 min. The reaction mixture was added with ice, theprecipitated solid was filtered and dried to afford4-bromo-2-nitrophenol (6 g, 95.23%) as yellow solid.

LCMS: 217 [M+1]⁺

Step 2: Synthesis of 2-amino-4-bromophenol

To a solution of 4-bromo-2-nitrophenol (3 g, 13.76 mmol, 1 eq.) inethanol-water (50 mL) was added ammonium chloride (2.1 g, 41.28 mmol, 3eq.) and iron (2.3 g, 41.28 mmol. The reaction was stirred at 90° C. for2 h. The reaction was monitored by LCMS and found to be complete after 2h. The reaction mixture was cooled to RT, evaporated under reducedpressure to remove the solvent diluted with water (20 mL) and extractedwith ethyl acetate (2×50 mL). Combined organic layer was washed withbrine (20 mL) and dried over sodium sulfate. Removal of solvent underreduced pressure gave crude which was purified by Combi-Flash to obtainthe 2-amino-4-bromophenol (2 g, 80%) as brown solid.

LCMS: 188 [M+1]⁺

Step 3: Synthesis of 5-bromobenzo[d]oxazole

A solution of 2-amino-4-bromophenol (1.5, 7.90 mmol, 1 eq.) inmethylorthoformate (10 mL) was stirred at 150° C. for 4-6 h. Thereaction was monitored by LCMS and found to be complete after 6 h. Thereaction mixture was cooled to RT, evaporated under reduced pressure toremove the solvent diluted with water (20 mL) and extracted with ethylacetate (2×50 mL). Combined organic layer was washed with brine (20 mL)and dried over sodium sulfate. Removal of solvent under reduced pressuregave crude which was purified by Combi-Flash to obtain the5-bromobenzo[d]oxazole (1.2 g, 80.0%) as yellow solid.

LCMS: 298 [M+1]⁺

Step 4: Synthesis of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole

To a solution of 5-bromobenzo[d]oxazole (1.2 g, 6.06 mmol, 1 eq.) in DMF(10 mL) was added 5-(4,4,5,5-bis(pinacolato)diboron (1.68 g, 1.66 mmol,1.1 eq.), KOAc (1.7 g, 18.09 mmol, 3 eq.), PdCl₂(dppf).DCM (247 mg, 0.23mmol, 0.05 eq.). The reaction mixture was deoxygenated with N₂ and thereaction mixture was stirred at 80° C. overnight. The reaction wasmonitored by LCMS and found to be complete after 18 h. The reactionmixture was cooled to RT, diluted with water (50 mL) and extracted withethyl acetate (2×50 mL). Combined organic layer was washed with brine(20 mL) and dried over sodium sulfate. Removal of solvent under reducedpressure gave crude which was purified by Combi-Flash (0-100%EtOAC-Hexane) to afford the desired product (900 mg, 60%) as off whitesolid.

LCMS: 246 [M+1]

Step 5: Synthesis of6-(benzo[d]oxazol-5-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one

To a solution of 6-bromo-7-phenylquinolin-4(1H)-one (100 mg, 0.40 mmol,1 eq.) in DME-water (2 mL) was added5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (97 mg,0.39 mmol, 1.2 eq.), Na₂CO₃ (70 mg, 0.66 mmol, 2.0 eq.), PdCl2(dppf).DCM(13.86 mg, 0.01 mmol, 0.05 eq.). The reaction mixture was deoxygenatedwith N₂ and the reaction mixture was stirred at 100° C. for 12 h. Thereaction was monitored by LCMS and found to be complete after 12 h. Thereaction mixture was cooled to RT, diluted with water (20 mL) andextracted with ethyl acetate (2×50 mL). Combined organic layer waswashed with brine (20 mL) and dried over sodium sulfate. Removal ofsolvent under reduced pressure gave crude which was purified by reversephase column chromatography to afford the desired product (10 mg, 9%) asoff white solid.

LCMS: 340 [M+1]⁺

¹HNMR (400 MHz, DMSO-d₆) δ 12.40 (s, 1H), 8.72 (s, 1H), 8.40 (s, 1H),8.20-8.00 (m, 2H), 7.70-7.62 (m, 2H), 7.40-7.20 (m, 5H), 6.18 (d, 1H).

Example S22. Synthesis of6-(1-methyl-1H-benzo[d]imidazol-5-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one(Compound No. 1.22)

Step 1: Synthesis of1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole

To a solution of 5-bromo-1-methyl-1H-benzo[d]imidazole (200 mg, 0.33mmol, 1 eq.) in 1,4-dioxane (10 mL) was added5-(4,4,5,5-bis(pinacolato)diboron (287 mg, 1.13 mmol, 1.2 eq.), KOAc(276 mg, 2.82 mmol, 2 eq.), PdCl₂(dppf).DCM (76 mg, 0.09 mmol, 0.09eq.). The reaction mixture was deoxygenated with N₂ and the reactionmixture was stirred at 80° C. for 16 h. The reaction was monitored byLCMS and found to be complete after 18 h. The reaction mixture wascooled to RT, diluted with water (50 mL) and extracted with ethylacetate (2×50 mL). Combined organic layer was washed with brine (20 mL)and dried over sodium sulfate. Removal of solvent under reduced pressuregave crude which was purified by Combi-Flash (0-100% EtOAC-Hexane) toafford the desired product (120 mg, 49%) as brown oil.

LCMS: 259 [M+1]⁺

Step 2: Synthesis of6-(1-methyl-1H-benzo[d]imidazol-5-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one

To a solution of 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one (100 mg,0.40 mmol, 1 eq.) in DME-water (2 mL) was added1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole(102 mg, 0.39 mmol, 1.2 eq.), K₂CO₃ (136 mg, 0.99 mmol, 3 eq.),PdCl₂(dppf).DCM (53 mg, 0.06 mmol, 0.2 eq.). The reaction mixture wasdeoxygenated with N₂ and the reaction mixture was stirred at 120° C. for30 min microwave irradiation. The reaction was monitored by LCMS andfound to be complete after 30 min. The reaction mixture was cooled toRT, diluted with water (20 mL) and extracted with ethyl acetate (2×50mL). Combined organic layer was washed with brine (20 mL) and dried oversodium sulfate. Removal of solvent under reduced pressure gave crudewhich was purified by reverse phase column chromatography to afford thedesired product (10 mg, 10%) as off white solid.

LCMS: 353 [M+1]⁺

¹HNMR (400 MHz, DMSO-d₆) δ 8.56 (s, 2H), 8.00 (s, 1H), 7.98-7.80 (m,2H), 7.65 (m, 1H), 7.40-7.20 (m, 5H), 6.80 (s, 2H).

Example S23. Synthesis of6-(8-methylquinolin-6-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one (CompoundNo. 1.23)

Step 1: Synthesis of8-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

To a solution of 6-bromo-8-methylquinoline (100 mg, 0.45 mmol, 1 eq.) in1,4-dioxane (10 mL) was added 5-(4,4,5,5-bis(pinacolato)diboron (127 mg,0.49 mmol, 1.1 eq.), KOAc (88 mg, 0.90 mmol, 2 eq.), PdCl₂(PPh₃)₂(15.7mg, 0.02 mmol, 0.05 eq.). The reaction mixture was deoxygenated with N₂and the reaction mixture was heated under microwave irradiation for 30min at 120° C. The reaction was monitored by LCMS and found to becomplete after 30 min. The reaction mixture was cooled to RT, dilutedwith water (10 mL) and extracted with ethyl acetate (2×20 mL). Combinedorganic layer was washed with brine (20 mL) and dried over sodiumsulfate. Removal of solvent under reduced pressure gave crude (150 mg)which was carried to next step without any further purification.

LCMS: 269 [M+1]⁺

Step 2: Synthesis of6-(8-methylquinolin-6-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one

To a solution of 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one (100 mg,0.33 mmol, 1 eq.) in DME-Water (2 mL) was added8-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (107mg, 0.39 mmol, 1.2 eq.), Na₂CO₃ (70 mg, 0.66 mmol, 2.0 eq.),PdCl₂(dppf).DCM (13. mg, 0.01 mmol, 0.05 eq.). The reaction mixture wasdeoxygenated with N₂ and the reaction mixture was stirred at 120° C. for30 min under Microwave irradiation. The reaction was monitored by LCMSand found to be complete after 30 min. The reaction mixture was cooledto RT, diluted with water (20 mL) and extracted with ethyl acetate (2×50mL). Combined organic layer was washed with brine (20 mL) and dried oversodium sulfate. Removal of solvent under reduced pressure gave crudewhich was purified by reverse phase column chromatography to afford thedesired product (10 mg, 8%) as off white solid.

LCMS: 364 [M+1]⁺

¹HNMR (400 MHz, DMSO-d₆) δ 12.40 (s, 1H), 8.96 (d, 1H), 8.58 (d, 1H),8.35 (d, 1H), 8.00 (d 1H), 7.80 (m, 1H), 7.50-7.20 (m, 7H), 6.20 (d,1H), 2.60 (s, 3H).

Example S24. Synthesis of6-(benzo[d]thiazol-6-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one (CompoundNo. 1.24)

To a solution of 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one (100 mg,0.40 mmol, 1 eq.) in dioxane-water (10 mL) was addedbenzo[d]thiazol-6-ylboronic acid (86.0 mg, 0.48 mmol, 1.2 eq.), Na₂CO₃(87 mg, 0.82 mmol, 2.5 eq.), and PdCl₂(dppf).DCM (13.4 mg, 0.01 mmol,0.05 eq.). The reaction mixture was deoxygenated with N₂ and thereaction mixture was stirred at 120° C. for 30 min under microwaveirradiation. The reaction mixture was cooled to RT, diluted with water(20 mL) and extracted with ethyl acetate (2×50 mL). Combined organiclayer was washed with brine (20 mL) and dried over sodium sulfate.Removal of solvent under reduced pressure gave crude which was purifiedby reverse phase column chromatography to afford the desired product (3mg 10%) as a light brown solid.

LCMS: 356 [M+1]⁺

¹HNMR (400 MHz, DMSO-d₆) δ 12.40 (s, 1H), 9.40 (s, 1H), 8.50 (s, 1H),8.20 (s, 1H), 8.15-8.00 (m 2H), 7.43-7.18 (m, 6H), 6.20 (d, 1H).

Example S25. Synthesis of7-(5-methylfuran-2-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one(Compound No. 1.25)

Step 1: Synthesis of 2-amino-6-chloro-N-methoxy-N-methylnicotinamide

To a stirred solution of 2-amino-6-chloronicotinic acid (1.136 g, 6.56mmol, 1.0 eq) and N,O-dimethylhydroxylamine hydrochloride (0.965 g, 9.85mmol, 1.5 eq) in DMF (20 mL) was added EDC (1.9 g, 9.85 mmol, 1.5 eq),HOBt (1.5 g, 9.85 mmol, 1.5 eq), and DIPEA (2.58 g, 20.0 mmol, 3.0 eq).The reaction was allowed to stir at RT for 16 h. The reaction mixturewas then extracted using ethyl acetate (2×100 mL). the combined organiclayer was washed (brine), dried (anhydrous sodium sulphate) andconcentrated under vacuum to get the solid which was purified by normalphase flash column chromatography to get the desired product (1.0 g)

LCMS: 216 [M+1]⁺

Step 2: Synthesis of 1-(2-amino-6-chloropyridin-3-yl)ethanone

To a solution of 2-amino-6-chloro-N-methoxy-N-methylnicotinamide (500mg, 2.32 mmol, 1.00 eq) in THF (20 mL) was cooled to 0° C. and 3M MeMgBrin THF (2.713 mL, 3.5 mmol) was added at the same temperature. Thereaction mixture was stirred at the same temperature for 30 min.Following this the reaction mixture was quenched using freshly preparedsaturated solution of NH₄Cl (50 mL) and extracted using ethyl acetate(2×50 mL). The combined organic layer was dried over sodium sulfate andconcentrated under reduced pressure to afford the desired product (300mg, 47%).

LCMS: 171 [M+1]⁺

Step 3: Synthesis of 1-(2-amino-5-bromo-6-chloropyridin-3-yl)ethanone

To a solution of 1-(2-amino-6-chloropyridin-3-yl)ethanone (1.5 g, 8.82mmol, 1 eq.) in mixture of ACN (50 mL) was added N-bromosuccinimide(1.895 g, 10.58 mmol, 1.2 eq.). The reaction mixture was stirred at roomtemperature for 1 h. The reaction was monitored by TLC and NMR. Thereaction solvent was evaporated under reduced pressure. The reactionmixture was diluted with water (100 mL) and extracted by ethyl acetate(2×50 mL). The organic layer was separated, washed water (5×20 mL) andbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure to afford (1.800 g, 85%) of1-(2-amino-5-bromo-6-chloropyridin-3-yl)ethanone.

LCMS: 249 [M+1]⁺

Step 4: Synthesis of1-(2-amino-6-chloro-5-(quinolin-6-yl)pyridin-3-yl)ethanone

To a solution of 1-(2-amino-5-bromo-6-chloropyridin-3-yl)ethanone (1.100g, 4.40 mmol, 1 eq.) in DME (10 mL): water (1 mL) was addedquinolin-6-ylboronic acid (0.756 g, 4.39 mmol, 1.0 eq.), K₂CO₃ (0.912 g,6.6 mmol, 1.5 eq.), PdCl₂(dppf).DCM (0.179 g, 0.22 mmol, 0.05 eq.). Thereaction mixture was deoxygenated using N₂ atmosphere and the reactionmixture was heated at 140° C. for 30 min. The reaction was monitored byTLC and LCMS. The reaction mixture was diluted with water (50 mL) andextracted using ethyl acetate (2×50 mL). The separated organic layer wasdried over sodium sulfate and concentrated under reduced pressure. Thecrude product was purified by flash column chromatography to afford thedesired product (350 mg, 26%).

LCMS: 298 [M+1]⁺

Step 5: Synthesis of1-(2-amino-6-(5-methylfuran-2-yl)-5-(quinolin-6-yl)pyridin-3-yl)ethanone

To a solution of1-(2-amino-6-chloro-5-(quinolin-6-yl)pyridin-3-yl)ethanone (200 mg, 0.67mmol, 1 eq.) in DME (8 mL): water (2 mL) was added5-methylfuran-2-ylboronic acid (109 mg, 0.87 mmol, 1.3 eq.), K₂CO₃ (139mg, 1.006 mmol, 1.5 eq.), PdCl₂(dppf).DCM (27 mg, 0.03 mmol, 0.05 eq.).The reaction mixture was deoxygenated using N₂ atmosphere and thereaction mixture was heated at 110° C. for 1 h. The reaction wasmonitored by TLC and LCMS. The reaction mixture was diluted with water(50 mL) and extracted using ethyl acetate (2×50 mL). The separatedorganic layer was dried over sodium sulfate and concentrated underreduced pressure. The crude product was purified by flash columnchromatography to afford the desired product (160 mg, 69%).

LCMS: 344 [M+1]⁺

Step 6: Synthesis of(E)-N′-(3-acetyl-6-(5-methylfuran-2-yl)-5-(quinolin-6-yl)pyridin-2-yl)-N,N-dimethylformimidamide

To a solution of1-(2-amino-6-(5-methylfuran-2-yl)-5-(quinolin-6-yl)pyridin-3-yl)ethanone(100 mg, 0.29 mmol, 1 eq), in 1,4-dioxane (5 mL), was added DMF:DMA (346mg, 2.91 mmol, 2.5 eq.). The reaction mixture was heated at 90° C. for30 min. The reaction was monitored by TLC and LCMS. The reaction solventwas evaporated under reduced pressure to afford the desired product (100mg, 86%).

LCMS: 399 [M+1]⁺

Step 7: Synthesis of7-(5-methylfuran-2-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one

To a solution ofN′-(3-acetyl-6-(5-methylfuran-2-yl)-5-(quinolin-6-yl)pyridin-2-yl)-N,N-dimethylformimidamide(100 mg, 0.25 mmol, 1 eq), in DMF (1 mL), was added Cs₂CO₃ (122 mg, 0.37mmol, 1.5 eq). The reaction mixture was heated at 90° C. for 18 h. Thereaction was monitored by LCMS. The reaction mixture was diluted withice cold water (25 mL). The precipitation of product was observed andfiltered as sold. The crude product was submitted to reverse phasecolumn chromatography to afford the desired product (10 mg, 11%).

LCMS: 354 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 3.20 (s, 3H), 5.98 (d, 1H), 6.10 (m, 2H),7.60 (m, 1H), 7.70 (d, 1H), 7.98 (d, 1H), 8.05 (m, 2H), 8.30 (s, 1H),8.42 (d, 1H), 8.98 (d, 1H), 12.40 (bs, 1H).

Example S26. Synthesis of6-(8-methoxyquinolin-6-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one (CompoundNo. 1.26)

Step 1: Synthesis of 8-methoxyquinolin-6-ylboronic acid

To a solution of 6-6-bromo-8-methoxyquinoline (200 mg, 084 mmol, 1 eq.)in 1,4-dioxane (10 mL) was added 5-(4,4,5,5-bis(pinacolato)diboron (256mg, 1.00 mmol, 1.2 eq.), KOAc (164 mg, 1.68 mmol, 2 eq.),PdCl₂(PPh₃)₂(68 mg, 0.168 mmol, 0.2 eq.). The reaction mixture wasdeoxygenated with N₂ and the reaction mixture was heated at 80° C. for12 h. The reaction was monitored by LCMS and found to be complete after12 h. The reaction mixture was cooled to RT, diluted with water (10 mL)and extracted with ethyl acetate (2×20 mL). Combined organic layer waswashed with brine (20 mL) and dried over sodium sulfate. Removal ofsolvent under reduced pressure gave crude which was carried to next stepwithout any purification to afford 8-methoxyquinolin-6-ylboronic acid.(120 mg) which was used directly to the next step.

LCMS: 204 [M+1]⁺

Step 2: Synthesis of6-(8-methoxyquinolin-6-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one

To a solution of 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one (100 mg,0.33 mmol, 1 eq.) in DME-water (2 mL) was added8-methoxyquinolin-6-ylboronic acid (80.9 mg, 0.39 mmol, 1.2 eq.), K₂CO₃(136.62 mg, 0.99 mmol, 3.0 eq.), PdCl₂(dppf).DCM (13.4 mg, 0.01 mmol,0.05 eq.). The reaction mixture was deoxygenated with N₂ and thereaction mixture was stirred at 120° C. for 30 min in microwave. Thereaction was monitored by LCMS and found to be complete after 30 min.The reaction mixture was cooled to RT, diluted with water (20 mL) andextracted with ethyl acetate (2×50 mL). Combined organic layer waswashed with brine (20 mL) and dried over sodium sulfate. Removal ofsolvent under reduced pressure gave crude which was purified by reversedphase column chromatography to afford the desired product (10 mg, 8%) asoff white solid.

LCMS: 380 [M+1]⁺

¹HNMR (400 MHz, DMSO-d₆) δ 12.40 (s, 1H), 8.82 (d, 1H), 8.60 (s, 1H),8.30 (d, 1H), 8.00 (d, 1H), 7.60-7.20 (m, 7H), 6.80 (s, 1H), 6.20 (d,1H), 3.60 (s, 3H).

Example S27. Synthesis of6-(1H-benzo[d]imidazol-5-yl)-7-(furan-2-yl)-1,8-naphthyridin-4(1H)-one(Compound No. 1.27)

To a solution of 6-bromo-7-(furan-2-yl)-1,8-naphthyridin-4(1H)-one (100mg, 0.33 mmol, 1 eq.) in DME-water (2 mL) was added8-methoxyquinolin-6-ylboronic acid (80.9 mg, 0.39 mmol, 1.2 eq.), K₂CO₃(136.62 mg, 0.99 mmol, 3.0 eq.), PdCl₂(dppf).DCM (13.4 mg, 0.01 mmol,0.05 eq.). The reaction mixture was deoxygenated with N₂ and thereaction mixture was stirred at 120° C. for 30 min under microwaveirradiation. The reaction was monitored by LCMS and found to be completeafter 30 min. The reaction mixture was cooled to room temperature,diluted with water (20 mL) and extracted with ethyl acetate (2×50 mL).Combined organic layer was washed with brine (20 mL) and dried oversodium sulfate. Removal of solvent under reduced pressure gave crudewhich was purified by reverse phase column chromatography to afford thedesired product (3 mg, 8%) as off-white solid.

LCMS: 329 [M+1]⁺

¹HNMR (400 MHz, DMSO-d₆) δ 8.56 (s, 2H), 8.00 (s, 1H), 7.98-7.80 (m,2H), 7.65 (m, 1H), 7.40-7.20 (m, 5H), 6.80 (s, 2H).

Example S28. Synthesis of7-(pyridin-3-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one (CompoundNo. 1.28)

Step 1: Synthesis of1-(6-amino-3-(quinolin-6-yl)-2,3′-bipyridin-5-yl)ethanone

To a solution of1-(2-amino-6-chloro-5-(quinolin-6-yl)pyridin-3-yl)ethanone (100 mg, 0.33mmol, 1 eq.) in DME (8 mL): water (2 mL) was added pyridin-3-ylboronicacid (49 mg, 0.40 mmol, 1.2 eq.), K₂CO₃ (69 mg, 0.50 mmol, 1.5 eq.),PdCl₂(dppf).DCM (13 mg, 0.015 mmol, 0.05 eq.). The reaction mixture wasdeoxygenated using N₂ atmosphere and the reaction mixture was heated at80° C. for 18 h. The reaction was monitored by TLC and LCMS. Thereaction mixture was diluted with water (50 mL) and extracted usingethyl acetate (2×50 mL). The separated organic layer was dried oversodium sulfate and concentrated under reduced pressure, to get thedesired product (200 mg) which was used as such for next step withoutfurther purification.

LCMS: 341 [M+1]⁺

Step 2: Synthesis of7-(pyridin-3-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one

To a solution of1-(6-amino-3-(quinolin-6-yl)-2,3′-bipyridin-5-yl)ethanone (200 mg, 0.58mmol, 1.00 eq.), in 1,4 dioxane (5 mL), was added DMF:DMA (346 mg, 2.91mmol, 2.5 eq.). The reaction mixture was heated at 90° C. for 30 min.The reaction was monitored by TLC and LCMS. The reaction solvent wasevaporated under reduced pressure. The semisolid crude material obtainedwas dissolved in DMF (2 mL) and Cs₂CO₃ (246 mg, 0.75 mmol, 1.5 eq.) wasadded. The reaction mixture was again heated at 90° C. for 18 h. Theprogress of the reaction was monitored by LCMS. The reaction mixture wasdiluted with ice cold water (25 mL) and the precipitates obtained werefiltered under vacuum. The residue was purified by reversed phase columnchromatography to afford the desired product (10 mg, 6%).

LCMS: 351 [M+1]⁺

¹H NMR (400 MHz, DMSO-d₆) δ 6.20 (d, 1H), 7.38 (t, 1H), 7.50 (d, 1H),7.58 (d, 1H), 7.78 (d, 1H), 7.90 (d, 1H), 8.02 (m, 2H), 8.38 (d, 1H),8.50-8.60 (d, 1H), 8.58 (m, 2H), 8.98 (d, 1H), 12.42 (bs, 1H).

Example S29. Synthesis of7-(5-methylfuran-2-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-2(1H)-one(Compound No. 1.29)

Step 1: Synthesis of (2-amino-6-chloropyridin-3-yl)methanol

To a stirred solution of 2-amino-6-chloro-N-methoxy-N-methylnicotinamide(1.0 g, 4.6 mmol, 1.0 eq) in THF (20 mL) was added 1M solution ofDIBAL-H in toluene (23.14 mL, 5.0 eq) dropwise at 0° C. Progress of thereaction was monitored by TLC. To the reaction mixture was added aqueousNH₄Cl and extracted using ethyl acetate (3×75 mL). Combined organiclayers were washed (brine), dried (anhydrous Na₂SO₄) and concentratedunder vacuum to get the solid which was further triturated with pentaneto give the desired product (0.330 g, 45%)

LCMS: 159 [M+1]⁺

Step 2: Synthesis of 2-amino-6-chloronicotinaldehyde

To a solution of (2-amino-6-chloropyridin-3-yl)methanol (2.67 g, 16.83mmol, 1.0 eq) in DCM (40 mL) was added PCC (7.26 g, 33.6 mmol, 2.0 eq)at 0° C., the reaction was allowed to stir at RT, progress of thereaction was monitored by TLC. After completion of the reaction thereaction was filtered through Celite. The filtrate were washed withbrine and dried over sodium sulphate and concentrated under vacuum toget the desired product (1.92 g, 73%).

LCMS: 157 [M+1]⁺

Step 3: Synthesis of 2-amino-5-bromo-6-chloronicotinaldehyde

To a stirred solution of 2-amino-6-chloronicotinaldehyde (1.8 g, 1.0 eq,11.49 mmol) in ACN (20 mL) were added NBS (2.0 g, 1.0 eq, 11.49 mmol) at0° C. The reaction mixture was allowed to stir at RT. The progress ofthe reaction was monitored by TLC. After complete conversion of thestarting material the reaction mixture was concentrated under vacuum.Water was added and the reaction mixture was extracted using ethylacetate (3×75 mL), the combined organics were washed with brine anddried over anhydrous sodium sulphate and concentrated under vacuum toget the desired product (1.8 g, 67%).

LCMS: 235 [M+1]⁺

Step 4: Synthesis of ethyl(E)-3-(2-amino-5-bromo-6-chloropyridin-3-yl)acrylate

In a 20 mL THF, NaH (1.8 g, 1.0 eq, 7.6 mmol) and TEPA (1.98 mL, 9.9mmol, 1.3 eq) was added at 0° C. Followed by addition of2-amino-5-bromo-6-chloronicotinaldehyde (1.8 g, 1.0 eq, 7.6 mmol) andthe reaction mixture was allowed to stir at RT. The progress of thereaction was monitored by TLC. The reaction was quenched by adding waterextracted by using ethyl acetate (3×100 mL). The combined organics werewashed by brine and dried over sodium sulphate and concentrated undervacuum to give the desired product (1.035 g, 34%)

LCMS: 305 [M+1]⁺

Step 5: Synthesis of 6-bromo-7-chloro-1,8-naphthyridin-2(1H)-one

To a freshly prepared sodium ethoxide (0.105 g Na metal in 10 mLethanol) at 0° C. was added 20 mL solution of ethyl(E)-3-(2-amino-5-bromo-6-chloropyridin-3-yl)acrylate (1.035 g, 4.56mmol, 1.0 eq) in ethanol and the reaction mixture was allowed to stir atRT for 16 h. The progress of the reaction was monitored by TLC. Thereaction mixture was concentrated under vacuum and extracted with ethylacetate (3×75 mL), the combined organic layers were washed with brineand dried over sodium sulphate and concentrated under vacuum to get thedesired product (0.650 g, 55%)

LCMS: 259 [M+1]⁺

Step 6: Synthesis of7-chloro-6-(quinolin-6-yl)-1,8-naphthyridin-2(1H)-one

To a stirred solution of 6-bromo-7-chloro-1,8-naphthyridin-2(1H)-one(0.120 g, 0.46 mmol, 1.0 equiv) and quinolin-6-ylboronic acid (0.096 g,0.56 mmol, 1.2 equiv) in dioxane (3 mL) was added Na₂CO₃ (0.097 g, 0.66mmol, 2.0 equiv) and 1 mL water. The reaction was purged with N₂ for 5min. To this reaction mixture was added Pd(dppf)Cl₂.DCM complex (0.019g, 5 mol %) and N₂ was purged again for another 5 min. The reactionmixture was heated at 70° C. for 16 h. The reaction mixture was allowedto cool to RT and extracted using ethyl acetate (2×35 mL). The combinedorganic layers were washed (brine), dried (anhydrous Na₂SO₄) andconcentrated under vacuum. The light brown solid obtained was trituratedwith pentane to give the desired product (0.100 g) which was used assuch for next step without further purification.

LCMS: 308 [M+1]⁺

Step 7: Synthesis of7-(5-methylfuran-2-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-2(1H)-one

To a stirred solution of7-chloro-6-(quinolin-6-yl)-1,8-naphthyridin-2(1H)-one (0.100 g, 0.32mmol, 1.0 equiv) and (5-methylfuran-2-yl)boronic acid (0.050 g, 0.38mmol, 1.2 equiv) in dioxane (3 mL) was added Na₂CO₃ (0.062 g, 0.64 mmol,2.0 equiv) and 1 mL water. The reaction was purged with N₂ for 5 min. Tothis reaction mixture was added Pd(dppf)Cl₂.DCM complex (0.015 g, 5 mol%) and N₂ was purged again for another 5 min. The reaction mixture washeated at 110° C. for 1 h under microwave irradiation. The reactionmixture was allowed to cool to RT and extracted using ethyl acetate(2×35 mL). The combined organic layers were washed (brine), dried(anhydrous Na₂SO₄) and concentrated under vacuum to get the solidresidue which was purified by reversed phase column chromatography toget the desired product as off white solid (0.005 g, 5%).

LCMS: 354 [M+1]⁺

¹HNMR (400 MHz, METHANOL-d₄) δ 8.71 (d, J=2.63 Hz, 1H), 8.23 (d, J=7.45Hz, 1H), 7.88 (t, J=4.17 Hz, 2H), 7.77 (s, 1H), 7.79 (s, 1H), 7.48-7.58(m, 1H), 7.41 (dd, J=4.39, 8.33 Hz, 2H), 6.46 (d, J=9.65 Hz, 1H), 6.20(d, J=3.07 Hz, 1H), 5.82 (d, J=3.07 Hz, 1H), 1.76-1.92 (m, 3H)

Example S30. Synthesis of7-(3-methyl-1H-pyrazol-1-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one(Compound No. 1.92)

Step 1: Synthesis of7-chloro-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one

To a solution of 1-(2-amino-5-(quinolin-6-yl)pyridin-3-yl)ethanone (297mg, 0.83 mmol, 1 eq), in 1,4 dioxane (10 mL), in DMF:DMA (150 mg, 1.25mmol, 1.5 eq.). The reaction mixture was heated at 100° C. for 30 min.The reaction was monitored by TLC and LCMS. The reaction mixture wasconcentrated under reduced pressure. To this Cs₂CO₃ (820 mg, 2.5 mmol,3.0 eq) and DMF (1 mL) was added. The reaction mixture was heated at120° C. for 16 h. The reaction mixture was diluted with ice cold water(5 mL) and extracted with ethyl acetate (3×30 mL). The separated organiclayer was washed with water (5×20 mL). The organic layer was dried oversodium sulfate and concentrated under reduced pressure. The crudeproduct was purified by normal phase column chromatography to get thedesired product (120 mg, 47%).

LCMS: 308 [M+1]⁺

Step-2: Synthesis of7-(3-methyl-1H-pyrazol-1-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one

To a stirred solution of7-chloro-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one (120 mg, 0.39mmol, 1 eq.) in DMF (2 mL) was added 3-methyl-1H-pyrazole (320 mg, 3.9mmol, 10 eq.) and Cs₂CO₃ (380 mg, 1.16 mmol, 3 eq.). Resulting mixturewas heated at 90° C. for 48 h, progress of the reaction was monitored byTLC and LCMS. On completion of the reaction, the reaction mixture wasdiluted with water (30 mL) and extracted with ethyl acetate (50 mL×2).Combined organic layers were washed with water (100 mL×2), dried withanhydrous Na₂SO₄ and concentrated under vacuum to get the solid residuewhich was purified by reversed phase column chromatography to get thedesired product as off white solid (2 mg, 1%).

LCMS: 354 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.47 (s, 1H), 9.05 (br.s., 1H), 8.65 (s, 1H), 8.60 (s, 1H), 8.19 (br. s., 1H), 8.11 (br. s.,1H), 7.93-8.04 (m, 2H), 7.76 (s, 1H), 7.47 (d, J=8.33 Hz, 1H), 6.31 (d,J=2.19 Hz, 1H), 6.19 (d, J=7.45 Hz, 1H), 1.96 (s, 3H).

Example S31. Synthesis of6-(benzo[d]thiazol-6-yl)-7-(5-methylfuran-2-yl)-1,8-naphthyridin-4(1H)-one(Compound No. 1.98)

Step 1: Synthesis of1-(2-amino-6-(5-methylfuran-2-yl)pyridin-3-yl)ethanone

To a solution of 1-(2-amino-6-chloropyridin-3-yl)ethanone (600 mg, 3.52mmol, 1 eq.) in DME (15 mL): water (3 mL) was added5-methylfuran-2-ylboronic acid (485 mg, 3.88 mmol, 1.1 eq.), K₂CO₃ (731mg, 5.29 mmol, 1.5 eq.), PdCl₂(dppf)DCM (144 mg, 0.017 mmol, 0.05 eq.).The reaction mixture was deoxygenated using N₂ atmosphere and thereaction mixture was heated at 80° C. for 18 h. The reaction wasmonitored by TLC and LCMS. The reaction mixture was diluted with water(50 mL) and extracted using ethyl acetate (2×50 mL). The separatedorganic layer was dried over sodium sulfate and concentrated underreduced pressure. The crude product was purified using Combi-flashcolumn chromatography to afford the desired product (150 mg, 20%).

LCMS: 217 [M+1]⁺.

Step 2: Synthesis of1-(2-amino-5-bromo-6-(5-methylfuran-2-yl)pyridin-3-yl)ethanone

To a solution of 1-(2-amino-6-(5-methylfuran-2-yl)pyridin-3-yl)ethanone(150 mg, 0.69 mmol, 1 eq.) in mixture of ACN (10 mL) was addedN-bromosuccinimide (160 mg, 0.89 mmol, 1.3 eq.). The reaction mixturewas stirred at room temperature for 1 h. The reaction was monitored byTLC and NMR. The reaction solvent was evaporated under reduced pressure.The reaction mixture was diluted with water (100 mL) and extracted byethyl acetate (2×50 mL). The organic layer was separated, washed water(5×20 mL) and brine and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure to afford the desired product (200mg, 98%).

LCMS: 295 [M+1]⁺.

Step 3: Synthesis ofN′-(3-acetyl-5-bromo-6-(5-methylfuran-2-yl)pyridin-2-yl)-N,N-dimethylformimidamide

To a solution of1-(2-amino-5-bromo-6-(5-methylfuran-2-yl)pyridin-3-yl)ethanone (200 mg,0.677 mmol, 1 eq), in 1,4 dioxane (10 mL), was added DMF:DMA (201 mg,1.69 mmol, 2.5 eq.). The reaction mixture was heated at 80° C. for 60min. The reaction was monitored by TLC and LCMS. The reaction solventwas evaporated under reduced pressure. The crude product was used innext step.

LCMS: 350 [M+1]⁺.

Step 4: Synthesis of6-bromo-7-(5-methylfuran-2-yl)-1,8-naphthyridin-4(1H)-one

To a solution ofN′-(3-acetyl-5-bromo-6-(5-methylfuran-2-yl)pyridin-2-yl)-N,N-dimethylformimidamide(200 mg, 0.57 mmol, 1 eq), in DMF (2 mL), was added Cs₂CO₃ (278 mg, 0.85mmol, 1.5 eq). The reaction mixture was heated at 90° C. for 18 h. Thereaction was monitored by LCMS. The reaction mixture was diluted withice cold water (25 mL) and extracted with ethyl acetate (2×50 mL). Theseparated organic layer was washed with water (5×20 mL). The organiclayer was dried over sodium sulfate and concentrated under reducedpressure to afford (150 mg, 86%) of6-bromo-7-(5-methylfuran-2-yl)-1,8-naphthyridin-4(1H)-one.

LCMS: 305 [M+1]⁺.

Step 5: Synthesis of6-(benzo[d]thiazol-6-yl)-7-(5-methylfuran-2-yl)-1,8-naphthyridin-4(1H)-one

To a solution of6-bromo-7-(5-methylfuran-2-yl)-1,8-naphthyridin-4(1H)-one (100 mg, 0.33mmol, 1 eq.) in 1,4 dioxane (8 mL): water (2 mL) was addedbenzo[d]thiazol-6-ylboronic acid (64 mg, 0.36 mmol, 1.1 eq.), K₂CO₃ (68mg, 0.49 mmol, 1.5 eq.), Pd(PPh₃)₄(19 mg, 0.016 mmol, 0.05 eq.). Thereaction mixture was deoxygenated using N₂ atmosphere and the reactionmixture was heated at 80° C. for 18 h. The reaction was monitored by TLCand LCMS. The reaction mixture was diluted with water (50 mL) andextracted using ethyl acetate (2×50 mL). The separated organic layer wasdried over sodium sulfate and concentrated under reduced pressure. Thecrude product was purified using reverse phase column chromatography toafford the desired product as off-white solid (14 mg, 11%).

LCMS: 260 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) D 12.44 (d, J=4.82 Hz, 1H),9.47 (s, 1H), 8.20-8.28 (m, 2H), 8.15 (d, J=8.33 Hz, 1H), 7.92-7.97 (m,1H), 7.50 (dd, J=1.75, 8.33 Hz, 1H), 6.07-6.12 (m, 2H), 5.86 (d, J=3.51Hz, 1H), 2.20 (s, 3H).

Example S32. Synthesis of7-(1H-pyrazol-1-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one(Compound No. 1.99)

To a stirred solution of6-bromo-7-(1H-pyrazol-1-yl)-1,8-naphthyridin-2(1H)-one (0.100 g, 0.34mmol, 1.0 eq.) and quinolin-6-ylboronic acid (0.071 g, 0.41 mmol, 1.2eq.) in DME (3 mL) was added Na₂CO₃ (0.072 g, 0.68 mmol, 2.0 eq.) and 1mL water. The reaction was deoxygenated using N2 followed by addition ofPd(dppf)Cl₂.DCM complex (0.014 g, 5 mol %). The reaction mixture wasdeoxygenated again & heated at 100° C. for 16 h. The reaction mixturewas allowed to cool to RT and extracted using ethyl acetate (3×25 mL).The combined organic layers were washed (brine), dried (anhydrousNa₂SO₄) and concentrated under vacuum to get the solid residue which waspurified by reversed phase column chromatography to get the desiredproduct as off white solid (0.015 g, 13%)

LCMS: 340 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.85-8.95 (m, 1H), 8.48(s, 1H), 8.32 (d, J=7.89 Hz, 1H), 8.19 (br. s., 1H), 8.05 (d, J=9.21 Hz,1H), 7.81-7.93 (m, 2H), 7.46-7.59 (m, 2H), 7.31 (d, J=8.33 Hz, 1H), 6.67(d, J=9.65 Hz, 1H), 6.46 (br. s., 1H).

Example S33. Synthesis of7-(1H-pyrazol-1-yl)-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one(Compound No. 1.100)

Step 1

To a stirred solution of7-chloro-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one (90 mg, 0.29 mmol,1.0 equiv) & hydrazine hydrate (22 mg, 0.43 mmol, 1.5 equiv) in dioxane(5 mL). The resulting mixture was heated at 90° C. for 16 h. Thereaction mixture was allowed to cool to RT and concentrated under vacuumto get the solid residue (90 mg crude) which was used for next reactionwithout purification.

LCMS: 304 [M+1]⁺.

Step 2

To a stirred solution of7-hydrazinyl-6-(quinolin-6-yl)-1,8-naphthyridin-4(1H)-one (90 mg, 0.29mmol, 1.0 equiv) & 1,1,3,3-tetraethoxypropane (97 mg, 0.44 mmol, 1.5equiv) in dioxane (5 mL) was added 20% HCl in dioxane (0.3 ml). Thereaction mixture was heated at 90° C. for 16 h. Progress of the reactionwas monitored by LCMS. The reaction mixture was allowed to cool to RT &basified with solution of NaHCO₃ (10 mL) and extracted with ethylacetate (20 mL×2). The combined organic layers were washed with water(50 mL) and brine solution (50 mL), dried (anhydrous Na₂SO₄) &concentrated under vacuum to get the solid residue which was purified byreversed phase column chromatography to get the desired product (13 mg,13%).

LCMS: 340 [M+1]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (d, J=3.95 Hz, 1H),8.62 (s, 1H), 8.36 (d, J=8.33 Hz, 1H), 8.29 (d, J=2.19 Hz, 1H), 8.04 (d,J=7.45 Hz, 1H), 7.99 (br. s., 1H), 7.85 (d, J=8.33 Hz, 1H), 7.58-7.47(m, 2H), 7.29 (d, J=8.77 Hz, 1H), 6.49 (br. s., 1H), 6.16 (d, J=7.45 Hz,1H).

Example S34. Synthesis of3-phenyl-2-(quinazolin-6-yl)pyrido[2,3-b]pyrazin-8(5H)-one (Compound No.1.101)

To a stirred solution of 2-bromo-3-phenylpyrido[2,3-b]pyrazin-8(5H)-one(0.100 g, 0.33 mmol, 1.0 eq.) in DME (20.0 mL) was addedquinazolin-6-ylboronic acid (0.110 g, 0.43 mmol, 1.3 eq). The reactionmixture was deoxygenated using nitrogen gas. Pd(dppf)Cl₂ dcm complex(0.0.013 g, 0.05 eq 0.0.16 mmol) was then added. The reaction mixturewas again purged with nitrogen & heated at 120° C. for 2 hours inmicrowave. Progress of the reaction was monitored by TLC and LCMS.Reaction mixture was allowed to cool to RT & quenched by adding aq. NaOH& extracted using ethyl acetate (3×100 mL) The combined organic layerswere washed (brine), dried (anhydrous Na₂SO₄) & concentrated undervacuum to get the solid which was purified by normal phase columnchromatography to get the desired product (0.0092 g, 8%).

LCMS: 351 [M+1]⁺ ¹H NMR (400 MHz, DMSO-d₆) δ 12.41 (d, J=5.70 Hz, 1H),9.60 (s, 1H), 9.34-9.14 (m, 1H), 8.56 (s, 1H), 8.27 (d, J=1.75 Hz, 1H),7.99-8.08 (m, 1H), 7.84 (d, J=8.77 Hz, 1H), 7.65 (dd, J=8.77, 1.75 Hz,1H), 7.46-7.15 (m, 5H), 6.18 (d, J=7.45 Hz, 1H).

Example S35. Synthesis of6-(3a,7a-dihydro-1H-indazol-5-yl)-7-phenyl-1,8-naphthyridin-4(1H)-one(Compound No. 1.102)

To a stirred solution of 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one(0.150 g, 0.5 mmol, 1.0 eq.) and (1H-indazol-5-yl)boronic acid (0.146 g,0.6 mmol, 1.2 eq.) in dioxane (4 mL) was added Na₂CO₃ (0.106 g, 1.0mmol, 2.0 eq.) and 1 mL water. The reaction was purged with N₂ for 5min. To this reaction mixture was added with Pd(dppf)Cl₂.DCM complex(0.021 g, 5 mol %) and N₂ was purged again for another 5 min. Thereaction mixture was heated at 100° C. for 18 h. The reaction mixturewas allowed to cool to RT and extracted using ethyl acetate (3×25 mL).The combined organic layers were washed (brine), dried (anhydrousNa₂SO₄) and concentrated under vacuum to get the solid residue which waspurified by reversed phase column chromatography to get the desiredproduct as off white solid (0.005 g, 3%)

LCMS: 339 [M+1]+¹H NMR (400 MHz, DMSO-d₆) δ 13.11 (br. s., 1H), 12.33(br. s., 1H), 8.39 (s, 1H), 8.05 (br. s., 1H), 7.98 (br. s., 1H), 7.72(s, 1H), 7.33-7.46 (m, 3H), 7.28 (d, J=7.02 Hz, 2H), 7.08 (d, J=8.33 Hz,1H), 6.14 (d, J=7.45 Hz, 2H).

Example S36. Synthesis of6-(3-chlorophenyl)-7-phenyl-1,8-naphthyridin-4(1H)-one (Compound No.1.30)

To a solution of 6-bromo-7-phenyl-1,8-naphthyridin-4(1H)-one (100 mg,0.33 mmol, 1 eq.) in 1,4-dioxane (8 mL): water (2 mL) was added3-chlorophenylboronic acid (54 mg, 0.35 mmol, 1.05 eq.), Na₂CO₃ (70 mg,0.66 mmol, 2 eq.), and Pd(PPh₃)₄(9 mg, 0.008 mmol, 0.025 eq.). Thereaction mixture was deoxygenated using N₂ and was allowed to heat at80° C. for 18 h. The progress of the reaction was monitored by LCMS. Thereaction mixture was diluted with water (50 mL) and extracted usingethyl acetate (2×50 mL). The separated organic layer was dried oversodium sulfate and concentrated under reduced pressure. The crudeproduct was purified by reverse phase column chromatography to affordthe desired product (25 mg, 23%)

LCMS: 333 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 6.18 (d, 1H), 7.18 (d,1H), 7.30-7.40 (m, 8H), 8.00 (d, 1H), 8.40 (s, 1H).

Example S37. Synthesis of6-(3-chlorophenyl)-7-phenyl-1,8-naphthyridin-2(1H)-one (Compound No.1.31)

To a stirred solution of 6-bromo-7-phenyl-1,8-naphthyridin-2(1H)-one(0.120 g, 0.40 mmol, 1.0 equiv) and (3-chlorophenyl)boronic acid (0.075g, 0.48 mmol, 1.2 equiv) in dioxane (4 mL) was added 2M aqueous Na₂CO₃(0.085 g, 0.80 mmol, 2.0 equiv, 0.4 mL). The reaction was purged with N₂for 5 min. To this reaction mixture was added Pd(dppf)Cl₂-DCM complex(0.016 g, 5 mol %) and N₂ was purged again for another 5 min. Thereaction mixture was heated at 90° C. for 4 h. The reaction mixture wasallowed to cool to RT and extracted using ethyl acetate (2×35 mL). Thecombined organic layers were washed (brine), dried (anhydrous Na₂SO₄)and concentrated under vacuum to get the solid residue which waspurified by normal phase flash column chromatography (3% Methanol inDCM) to get the desired product as off white solid (0.020 g, 15%).

LCMS: 333 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (s, 1H), 8.00 (d,J=9.21 Hz, 1H), 7.22-7.42 (m, 8H), 7.06-7.17 (m, 1H), 6.63 (d, J=9.65Hz, 1H).

Example S38. Synthesis of6-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-7-phenyl-1,8-naphthyridin-2(1H)-one(Compound No. 1.32)

To a stirred solution of 6-bromo-7-phenyl-1,8-naphthyridin-2(1H)-one(0.120 g, 0.40 mmol, 1.0 equiv) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one(0.124 g, 0.48 mmol, 1.2 equiv) in dioxane (4 mL) was added 2M aqueousNa₂CO₃ (0.085 g, 0.80 mmol, 2.0 equiv, 0.4 mL). The reaction was purgedwith N₂ for 5 min. To this reaction mixture was added Pd(dppf)Cl₂-DCMcomplex (0.016 g, 5 mol %) and N₂ was purged again for another 5 min.The reaction mixture was heated at 90° C. for 4 h. The reaction mixturewas allowed to cool to RT and extracted using ethyl acetate (2×35 mL).The combined organic layers were washed (brine), dried (anhydrousNa₂SO₄) and concentrated under vacuum to get the solid residue which waspurified by reverse phase column chromatography to get the desiredproduct (0.020 g, 14%).

LCMS: 355 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (br. s., 2H), 8.13(s, 1H), 7.99 (d, J=9.65 Hz, 1H), 7.17-7.42 (m, 5H), 6.84 (d, J=7.89 Hz,1H), 6.71-6.78 (m, 2H), 6.60 (d, J=9.21 Hz, 1H).

Example S39. Synthesis of6-(2,6-dimethylpyridin-4-yl)-7-phenyl-1,8-naphthyridin-2(1H)-one(Compound No. 1.33)

To a stirred solution of 6-bromo-7-phenyl-1,8-naphthyridin-2(1H)-one(0.120 g, 0.40 mmol, 1.0 equiv) and (2,6-dimethylpyridin-4-yl)boronicacid (0.073 g, 0.48 mmol, 1.2 equiv) in dioxane (2 mL) was added Na₂CO₃(0.085 g, 0.80 mmol, 2.0 equiv) and 0.8 mL water. The reaction waspurged with N₂ for 5 min. To this reaction mixture was addedPd(dppf)Cl₂-DCM complex (0.016 g, 5 mol %) and N₂ was purged again foranother 5 min. The reaction mixture was heated at 90° C. for 4 h. Thereaction mixture was allowed to cool to RT and extracted using ethylacetate (2×35 mL). The combined organic layers were washed (brine),dried (anhydrous Na₂SO₄) and concentrated under vacuum to get the solidresidue which was purified by reverse phase column chromatography to getthe desired product as off white solid (0.020 g, 15%).

LCMS: 328 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.28 (br. s., 1H), 8.22(s, 1H), 8.00 (d, J=9.78 Hz, 1H), 7.26-7.44 (m, 5H), 6.86 (s, 2H), 6.63(d, J=9.29 Hz, 1H), 2.32 (s, 6H)

Example S40. Synthesis of7-phenyl-6-(pyridin-4-yl)-1,8-naphthyridin-2(1H)-one (Compound No. 1.34)

To a solution of 6-bromo-7-phenyl-1,8-naphthyridin-2(1H)-one (100 mg,0.33 mmol, 1 eq.) in 1,4-dioxane (8 mL): water (2 mL) was addedpyridin-4-ylboronic acid (41 mg, 0.33 mmol, 1.00 eq.), Na₂CO₃ (70 mg,0.66 mmol, 2 eq.), and PdCl₂(dppf)DCM complex (6 mg, 0.008 mmol, 0.025eq.). The reaction mixture was deoxygenated using N₂ atmosphere and thereaction mixture was heated at 80° C. for 18 h. The reaction wasmonitored by NMR and LCMS. The reaction mixture was diluted with water(50 mL) and extracted using ethyl acetate (2×50 mL). The separatedorganic layer was dried over sodium sulfate and concentrated underreduced pressure. The crude product was purified by reverse phase columnchromatography to afford (20 mg, 20%) as a desired product.

LCMS: 300 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 6.62 (d, 1H), 7.20 (d,2H), 7.30-7.40 (bs, 5H), 8.00 (d, 1H), 8.22 (s, 1H), 8.30 (d, 2H).

Example S41. Synthesis of6-(3-chloro-5-methylphenyl)-7-phenyl-1,8-naphthyridin-2(1H)-one(Compound No. 1.35)

To a solution of 6-bromo-7-phenyl-1,8-naphthyridin-2(1H)-one (100 mg,0.33 mmol, 1 eq.) in 1,4-dioxane (8 mL): water (2 mL) was added3-chloro-5-methylphenylboronic acid (41 mg, 0.33 mmol, 1.00 eq.), Na₂CO₃(70 mg, 0.66 mmol, 2 eq.), PdCl₂(dppf)DCM complex (6 mg, 0.008 mmol,0.025 eq.). The reaction mixture was deoxygenated using N₂ atmosphereand the reaction mixture was heated at 80° C. for 18 h. The reaction wasmonitored by NMR and LCMS. The reaction mixture was diluted with water(50 mL) and extracted using ethyl acetate (2×50 mL). The separatedorganic layer was dried over sodium sulfate and concentrated underreduced pressure. The crude product was purified by reverse phase columnchromatography to afford (20 mg, 17%) as a desired product.

LCMS: ([M+1]+): 347. ¹H NMR (400 MHz, DMSO-d₆) δ 2.20 (s, 3H), 6.60 (d,1H), 6.98-7.00 (d, 2H), 7.18 (s, 1H), 7.30-7.40 (s, 5H), 8.00 (s, 1H),8.20 (s, 1H).

It is understood that compounds from the Table-1 (1.36-1.91, 1.93-1.97and 1.103-2.023) may be synthesized by the General Synthetic Scheme 1,Scheme 2, Scheme 3, Scheme 4, Scheme 5 or present routes involving stepsclearly familiar to those skilled in the art, wherein the substituentsdescribed in compounds of formula (I) herein can be varied with a choiceof appropriate starting materials and reagents utilized in the stepspresented.

Biological Examples Example B1. Radioligand Binding Competition Assay

Binding of selected compounds to the adenosine A₁, A_(2A), A_(2B), andA₃ receptors was tested using a binding competition assay.

The general protocol for the radioligand binding competition assay wasas follows. Competition binding was performed in duplicate in the wellsof a 96 well plate (Master Block, Greiner, 786201) containing bindingbuffer (optimized for each receptor), membrane extracts (amount ofprotein/well optimized for each receptor), radiotracer (finalconcentration optimized for each receptor), and test compound.Nonspecific binding was determined by co-incubation with 200-fold excessof cold competitor. The samples were incubated in a final volume of 0.1mL at 25° C. for 60 minutes and then filtered over filter plates.Filters were washed six times with 0.5 mL of ice-cold washing buffer(optimized for each receptor) and 50 μL of Microscint 20 (Packard) wereadded on each filter. The filter plates were sealed, incubated 15 min onan orbital shaker and scintillation counted with a TopCount for 30sec/filter.

For the adenosine A_(2A) receptor radioligand binding assay, thefollowing modifications were made to the general protocol. GF/C filters(Perkin Elmer, 6005174), presoaked in 0.01% Brij for 2 h at roomtemperature were used. Filters were washed six times with 0.5 mL ofice-cold washing buffer (50 mM Tris pH 7.4) and 50 μL of Microscint 20(Packard) was added in each well. The plates were then incubated for 15min on an orbital shaker and then counted with a TopCount™ for 1min/well.

Another radioligand binding assay was used to evaluate the bindingaffinity for the adenosine A_(2A) receptor assay was performed induplicate in the wells of a 384 plate. Assay buffer contained DPBS 500mM, MgCl₂ 0.1 mM, and 1% DMSO. Membrane-bead suspension was prepared bymixing 25.98 μL of human adenosine A_(2A) membrane preparation (PerkinElmer, RBHA2AM400UA) at 33.4 pg/mL, 28 μL of ADA at 20 pg/mL, and 932 μLof SPA beads at 3.33 mg/mL) and incubated the mixture for 20 min at roomtemperature. Mixed 20 μL of radiotracer (³H-SCH 58261) at 15 nM to eachwell containing test articles at various concentrations and centrifugethe plate at 1000 rpm for 1 minute. Added 30 μL of the membrane-beadsuspension to each well. Sealed the plates and incubated for 1 hr atroom temperature with vigorous mixing on a plate mixer. Plates were readon Microbeta² (Perkin Elmer, 2450-0010).

For the adenosine A₁ radioligand binding competition assay, a similarprocedure was used except that the following reagents were used:CHO-K1-A1 cell membranes; binding buffer comprising HEPES 25 mM pH 7.4,MgCl₂ 5 mM, CaCl₂ 1 mM, NaCl 100 mM, saponin 10 g/mL; wash buffercomprising HEPES 25 mM pH 7.4, MgCl₂ 5 mM, CaCl₂ 1 mM, NaCl 100 mM;Unifilter GF/B—treated for 2 h with 0.5% PEI was the filter; and 1.6 nMof ³H-DPCPX was the tracer.

Similarly, the following reagents were used for the adenosine A_(2B)radioligand binding competition assay: HEK-293-A2b cell membranes, 20μg/well, preincubated 30 min at RT with g/mL Adenosine Deaminase; abinding buffer comprising HEPES 10 mM pH7.4, EDTA 1 mM, 0.5% BSA; a washbuffer comprising HEPES 10 mM pH7.4, EDTA 1 mM; a Unifilter GF/C—treatedfor 2 h with 0.5% PEI; and 10 nM ³H-DPCPX as the tracer.

For the adenosine A₃ radioligand binding competition assay, thefollowing reagents were used:

CHO-K1-A3 cell membranes, 1.5 μg/well; a binding buffer comprising HEPES25 mM pH 7.4, MgCl₂ 5 mM, CaCl₂ 1 mM, 0.5% BSA; a wash buffer comprisingHEPES 25 mM pH 7.4, MgCl₂ 5 mM, CaCl₂ 1 mM; a Unifilter GF/C—treated for2 h with 0.5% BS; and 0.4 nM of ¹²⁵I-AB-MECA as the tracer.The results of the binding assay are shown in Table B1-1 and are shownas percent residual binding at a given concentration. Percent ofresidual binding means binding of a compound in the presence ofcompetitor normalized to the amount of binding in the absence ofcompetitor. The compounds tested showed a range of binding to theadenosine receptors tested. For example, compound 1 strongly bound toA_(2A) (30% residual binding at a concentration of 100 nM), A₁ (−3%residual binding at 300 nM) and A_(2B), (−9% residual binding at 300 nM)but weakly bound to A₃ (96% residual binding at 300 nM).

TABLE B1-1 A_(2A) radioligand Radioligand binding binding competitioncompetition assay assay % residual % residual A_(2A) Compound binding @3000/ binding @ 300 nM binding No. 1000/300/100 nM (A₁/A_(2b)/A₃) IC₅₀(nM) 1.1 ND/ND/54/83 1.6/17/95 ND 1.2 ND/ND/60/77 0/0/83 ND 1.350/ND/ND/ND ND ND 1.4 19/17/79/71 ND ND 1.5 22/12/38/74 11/2/104 181 1.657/ND/ND/ND ND ND 1.7 18/21/33/52 7/0/84 ND 1.8 106/ND/ND/ND ND ND 1.970/ND/ND/ND ND ND 1.10 60/ND/ND/ND ND ND 1.11 51/ND/ND/ND ND ND 1.1214/ND/ND/ND ND ND 1.13 29/ND/ND/ND ND ND 1.14 5/ND/ND/ND 13/0/87  331.15 45/ND/ND/ND ND ND 1.16 76/ND/ND/ND ND ND 1.17 14/ND/ND/ND ND ND1.18 38/ND/ND/ND ND ND 1.19 25/ND/ND/ND ND ND 1.20 36/ND/ND/ND ND ND1.21 54/ND/ND/ND ND ND 1.22 69/ND/ND/ND ND ND 1.23 22/ND/ND/ND ND ND1.24 16/ND/ND/ND ND ND 1.25 0/ND/ND/ND ND ND ND = Not determined

TABLE B1-2 Compound A2a binding A2a binding % A2a binding % inh @ No.IC50 (nM) inh @ 3000 nM 1000/300/100/10/1 nM 1.98 ND 85 ND 1.99 ND 57 ND1.100 ND 78 ND 1.101 ND 72 ND 1.102 ND 77 ND 1.30 ND ND ND/0/ND/ND/ND1.31 ND ND ND/0/ND/ND/ND 1.32 ND ND ND/0/ND/ND/ND 1.33 ND 30 ND 1.34 ND30 ND 1.35 ND  0 ND ND = Not determined

Example B2. cAMP Assay

The functional activity of compounds was tested using one of the twoassays to detect the present of cAMP. Activation of G-protein coupledreceptors (such as A_(2A)) results in activation of adenylcyclase whichconverts ATP into cAMP which is used as a downstream signaling molecule.Therefore, molecules which act as GPCR (or specifically A_(2A) receptor)antagonists cause a decrease in intracellular cAMP concentration.

Both assays used HEK-293 cells expressing human recombinant adenosineA_(2A) receptor were grown prior to the test in media withoutantibiotic. Assay 1: The cells were detached by gentle flushing withPBS-EDTA (5 mM EDTA), recovered by centrifugation and suspended in assaybuffer (KRH: 5 mM KCl, 1.25 mM MgSO₄, 124 mM NaCl, 25 mM HEPES, 13.3 mMGlucose, 1.25 mM KH₂PO₄, 1.45 mM CaCl₂, 0.5 g/L BSA, supplemented withRolipram).

12 μL of cells were mixed with 6 μL of the test compound at increasingconcentrations and then incubated for 10 min. Thereafter 6 μL of thereference agonist was added at a final concentration corresponding tothe historical EC₈₀. The plates were then incubated for 30 min at roomtemperature. After addition of the lysis buffer and 1 hour incubation,cAMP concentrations were estimated, according to the manufacturerspecification, with the HTRF® kit.

Assay 2: 100 nL of test articles at 100× of final concentration weretransferred to assay plate by Echo. Cells were washed twice with 5 mL ofPBS 10 μL of cells were mixed with 5 mL PBS. After aspirating the PBSand adding 1.5 mL versine, cells were incubated at 37° C. for 2-5 min.After centrifugation, 4 mL of medium was added and adjusted cell densityto 5,000 cells/well with stimulation buffer. 10 μL of cells werealiquoted to the assay plate, centrifuged at 1000 rpm for 1 minute, andincubated for 60 minutes at room temperature. 5 μL 4× Eu-cAMP tracersolution and 5 μL 4× Ulight™-anti-cAMP solution were added to assayplate, followed by centrifugation and 60-minute incubation at roomtemperature. Plates were read on EnVision.

Compound No. A2a cAMP IC₅₀ (nM) A2a cAMP % inh @ 100 nM 1.1 61 ND 1.2 22ND 1.3 ND 50 1.4 ND 82 1.5 23 ND 1.6 ND 43 1.7 ND 81 1.8 ND  0 1.9 ND 301.10 ND 40 1.11 ND 49 1.12 ND 100  1.13   47.7 ND 1.14 ND 94 1.15 ND 541.16 ND 23 1.17 ND 85 1.18 ND 61 1.19 ND 74 1.20 ND 63 1.21 ND 45 1.22ND 30 1.23 ND 77 1.24 ND 83 1.25   18.8 ND 1.26 ND 64 1.27 ND 88 1.28 ND46 1.29 ND 77 ND = Not determined

Compound A2a cAMP A2a cAMP % No. IC₅₀ (nM) inh @ 300/100 nM 1.92 357 ND1.98 17.2 ND 1.99 7307 ND 1.100 3223 ND 1.101 181.8 ND 1.102 292.4 ND1.33 ND 60/ND 1.34 ND 26/ND 1.35 ND 12/ND ND = Not determined

Example B3: GTPγ³⁵S Scintillation Proximity Assay for A_(2A) Receptor

A scintillation proximity assay (SPA) can be used to determine thekinetic profile of the binding of candidate molecules to the A_(2A)receptor.

For antagonist testing, membranes extracts are prepared from HEK-293cells expressing recombinant human A_(2A) receptor are mixed with GDP(volume:volume) and are incubated in assay buffer comprising 20 mM HEPESpH 7.4; 100 mM NaCl, 10 μg/mL saponin, 5 mM MgCl₂ for at least 15 min onice. In parallel, GTPγ[³⁵S] is mixed with the beads (volume:volume) justbefore starting the reaction. The following reagents are successivelyadded in the wells of an Optiplate (Perkin Elmer): 25 μL of testcompound or reference ligand, 25 μL of the membranes: GDP mix, 25 μL ofreference agonist at historical EC₈₀ and 25 μL of GTPγ[³⁵S](PerkinElmerNEG030X), diluted in assay buffer to give 0.1 nM. The plate is incubatedat room temperature for 1 hour. Then, 20 μL of IGEPAL is added for 30minutes at room temperature. Following this incubation, 20 μL of beads(PVT-anti rabbit (PerkinElmer, RPNQ0016)), diluted in assay buffer at 50mg/mL (0.5 mg/10 μL) and 20 μL of an Anti-GαS/olf antibody are added fora final incubation of 3 hours at room temperature. Then the plates arecentrifuged for 10 min at 2000 rpm, incubated at room temperature for 1hour and counted for 1 min/well with a PerkinElmer TopCount reader.

Example B4: Human T Cell Activation Assay

Fresh human blood was diluted with the same volume of PBS and the buffycoat containing peripheral blood mononuclear cells (PBMCs) were preparedand resuspend in culture medium at a density of 2×10⁶/mL. 2×10⁵ PBMCs(in 100 μL) were plated to each well of 96-well flat bottom plate. 25 μLof 8× final concentration of 10-fold serial diluted compounds were addedto indicated wells and incubate for 30 mins in 37° C./5% CO2. Beadsincluded in T cell activation/expansion kit (Miltenyi biotecCat#130-091-441) at a bead-to-cell ratio of 1:6 in 50 L were added toall well with the final concentration of DMSO at 0.1% and final volumeat 200 μL. 60 μL of supernatant post 24 hr and 48 hr incubation wascollected for TNF-α and IFN-γ concentration evaluation using TNF-α ELISAready-set-go kit (eBioscience, Cat#88-7346-77) and IFN-γ ELISAready-set-go kit (eBioscience, Cat#88-7316-77), respectively.

Example B5: cAMP Assay

CD8+ T-cells are isolated from peripheral blood mononuclear cells (PBMC)from normal donors using CD8+T lymphocyte enrichment kit.

In a 96-well plate coated with anti-CD3 antibody, CD8⁺ T-cells (1×10⁵)were cultured alone, with 3 μM of NECA, or in the presence of 1 μM ofcompound of the interest with or without 3 μM of NECA. The cells wereincubated for 30 min at 37° C. and 5% CO₂, and the reaction was stoppedby addition of 200 μL, 0.1 M hydrochloric acid. cAMP levels weredetermined by an ELISA kit.

Example B6: Anti-Tumor Activities in Immuno-Oncology Mouse Models

The anti-tumor activities of test articles will be evaluated inselective mouse models (e.g., syngeneic model, xenograft modle, or PDX)as a monotherapy or combination therapies. Using MC-38 syngenic model asan example: female C57BL/6 mice are inoculated subcutaneously at rightflank with MC-38 cells for tumor development. Five days after tumorinoculation, mice with tumor size ranging from 40-85 mm³ are selectedand assigned into sub-groups using stratified randomization with 10 miceper group based upon their tumor volumes. Mice receive pre-definedtreatments include vehicle, test article at various doses alone, testarticle at various doses plus other anti-cancer therapy, and otheranti-cancer therapy contro. Body weight and tumor sizes are measuredthree times per week during the treatment. Tumor volume will beexpressed in mm³ using the formula: V=0.5 a×b² where a and b are thelong and short diameters of the tumor, respectively. The tumor sizes areused for the calculations of both tumor growth inhibition (TGI) and T/Cvalues. When an individual animal reaches to the termination endpoint(e.g., with TV>1000 mm³), the mouse are euthanized. The time frominoculation to the termination are deemed as its survival time. Survivalcurve are plotted by Kaplan-Meier method. At the end of study, plasmaand tumor samples are collected to explore biomarkers.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced in light of the aboveteaching. Therefore, the description and examples should not beconstrued as limiting the scope of the invention.

What is claimed is:
 1. A compound of Formula (I):

or a tautomer or isomer thereof, or a pharmaceutically acceptable saltof any of the foregoing, wherein: R¹ is H or C₁-C₆ alkyl wherein theC₁-C₆ alkyl of R¹ is optionally substituted with oxo or R^(a); R² is H,R^(b) or oxo; R⁴ is H, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, —CN, —OR⁸, —SR⁸, —NO₂, —C═NH(OR⁸), —C(O)R⁸, —OC(O)R⁸, —C(O)OR⁸,—C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁸C(O)OR⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸,—S(O)₂R⁸, —NR⁸S(O)R⁹, —C(O)NR⁸S(O)R⁹, —NR⁸S(O)₂R⁹, —C(O)NR⁸S(O)₂R⁹,—S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰, —P(O)(OR⁹)(OR¹⁰), C₃-C₆ cycloalkyl,3-12-membered heterocyclyl, 5- to 10-membered heteroaryl, C₆-C₁₄ aryl,—(C₁-C₃ alkylene)CN, —(C₁-C₃ alkylene)OR⁸, —(C₁-C₃ alkylene)SR⁸, —(C₁-C₃alkylene)NR⁹R¹⁰, —(C₁-C₃ alkylene)CF₃, —(C₁-C₃ alkylene)NO₂, —C═NH(OR⁸),—(C₁-C₃ alkylene)C(O)R⁸, —(C₁-C₃ alkylene)OC(O)R⁸, —(C₁-C₃alkylene)C(O)OR⁸, —(C₁-C₃ alkylene)C(O)NR⁹R¹⁰, —(C₁-C₃alkylene)OC(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)NR⁸C(O)R⁹, —(C₁-C₃alkylene)NR⁸C(O)OR⁹, —(C₁-C₃ alkylene)NR⁸C(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)R⁸, —(C₁-C₃ alkylene)S(O)₂R⁸, —(C₁-C₃ alkylene)NR⁸S(O)R⁹,—C(O)(C₁-C₃ alkylene)NR⁸S(O)R⁹, —(C₁-C₃ alkylene)NR⁸S(O)₂R⁹, —(C₁-C₃alkylene)C(O)NR⁸S(O)₂R⁹, —(C₁-C₃ alkylene)S(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)₂NR⁹R¹⁰, —(C₁-C₃ alkylene)P(O)(OR⁹)(OR¹⁰), —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-12-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-10-membered heteroaryl) or -(C₁-C₃alkylene)(C₆-C₁₄ aryl), each of which is independently optionallysubstituted by halogen, oxo, —OR¹¹, —NR¹¹R¹², —C(O)R¹¹, —CN, —S(O)R¹¹,—S(O)₂R¹¹, —P(O)(OR¹¹)(OR¹²), —(C₁-C₃ alkylene)OR¹¹, —(C₁-C₃alkylene)NR¹¹R¹², —(C₁-C₃ alkylene)C(O)R¹¹, —(C₁-C₃ alkylene)S(O)R¹¹,—(C₁-C₃ alkylene)S(O)₂R¹¹, —(C₁-C₃ alkylene)P(O)(OR¹¹)(OR¹²), C₃-C₈cycloalkyl, or C₁-C₆ alkyl optionally substituted by oxo, —OH orhalogen; R³ and R⁵ are each independently H or R^(c); each R^(a), R^(b),and R^(c) is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, —CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C═NH(OR⁸), —C(O)R⁸, —OC(O)R⁸,—C(O)OR⁸, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)OR⁹,—NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, —NR⁸S(O)R⁹, —C(O)NR⁸S(O)R⁹,—NR⁸S(O)₂R⁹, —C(O)NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰,—P(O)(OR⁹)(OR¹⁰), C₃-C₆ cycloalkyl, 3-12-membered heterocyclyl, 5- to10-membered heteroaryl, C₆-C₁₄ aryl, —(C₁-C₃ alkylene)CN, —(C₁-C₃alkylene)OR⁸, —(C₁-C₃ alkylene)SR⁸, —(C₁-C₃ alkylene)NR⁹R¹⁰, —(C₁-C₃alkylene)CF₃, —(C₁-C₃ alkylene)NO₂, —C═NH(OR⁸), —(C₁-C₃ alkylene)C(O)R⁸,—(C₁-C₃ alkylene)OC(O)R⁸, —(C₁-C₃ alkylene)C(O)OR⁸, —(C₁-C₃alkylene)C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)OC(O)NR⁹R¹⁰, —(C₁-C₃alkylene)NR⁸C(O)R⁹, —(C₁-C₃ alkylene)NR⁸C(O)OR⁹, —(C₁-C₃alkylene)NR⁸C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)S(O)R⁸, —(C₁-C₃alkylene)S(O)₂R⁸, —(C₁-C₃ alkylene)NR⁸S(O)R⁹, —C(O)(C₁-C₃alkylene)NR⁸S(O)R⁹, —(C₁-C₃ alkylene)NR⁸S(O)₂R⁹, —(C₁-C₃alkylene)C(O)NR⁸S(O)₂R⁹, —(C₁-C₃ alkylene)S(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)₂NR⁹R¹⁰, —(C₁-C₃ alkylene)P(O)(OR⁹)(OR¹⁰), —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-12-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-10-membered heteroaryl) or -(C₁-C₃alkylene)(C₆-C₁₄ aryl), wherein each R^(a), R^(b), and R^(c) isindependently optionally substituted by halogen, oxo, —OR¹¹, —NR¹¹R¹²,—C(O)R¹¹, —CN, —S(O)R¹¹, —S(O)₂R¹¹, —P(O)(OR¹¹)(OR¹²), —(C₁-C₃alkylene)OR¹¹, —(C₁-C₃ alkylene)NR¹¹R¹², —(C₁-C₃ alkylene)C(O)R¹¹,—(C₁-C₃ alkylene)S(O)R¹¹, —(C₁-C₃ alkylene)S(O)₂R¹¹, —(C₁-C₃alkylene)P(O)(OR¹¹)(OR¹²), C₃-C₈ cycloalkyl, or C₁-C₆ alkyl optionallysubstituted by oxo, —OH or halogen; wherein when R¹ is C₁-C₆ alkyl, R⁴is other than —NR⁹R¹⁰ and R³ is other than —C(O)R⁸; ------ is a singlebond or a double bond, wherein when ------ is a double bond, R² is oxo;

is a single bond or a double bond, wherein when

is a double bond, R⁴ is oxo; one of ------ and

is a double bond and the other is a single bond; A is C₆-C₁₂ aryl, 5- to10-membered heteroaryl, 9- to 10-membered carbocycle, or 9- to10-membered heterocycle, wherein the C₆-C₁₂ aryl, 5- to 10-memberedheteroaryl or 9- to 10-membered carbocycle, or 9- to 10-memberedheterocycle of A is optionally further substituted with R⁶; B is phenyl,5- to 6-membered heteroaryl, 5- to 6-membered carbocycle, 5- to6-membered heterocycle, or 9- to 10-membered heteroaryl, wherein thephenyl, 5- to 6-membered heteroaryl, 5- to 6-membered carbocycle, 5- to6-membered heterocycle, or 9- to 10-membered heteroaryl of B isoptionally further substituted with R⁷; wherein when B is 5- to6-membered heterocycle, A is other than phenyl optionally furthersubstituted with R⁶ or pyridyl optionally further substituted with R⁶;each R⁶ and R⁷ is independently oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, halogen, —CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C═NH(OR⁸), —C(O)R⁸,—OC(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)OR⁹,—NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, —NR⁸S(O)R⁹, —C(O)NR⁸S(O)R⁹,—NR⁸S(O)₂R⁹, —C(O)NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰,—P(O)(OR⁹)(OR¹⁰), C₃-C₆ cycloalkyl, 3-12-membered heterocyclyl, 5- to10-membered heteroaryl, C₆-C₁₄ aryl, —(C₁-C₃ alkylene)CN, —(C₁-C₃alkylene)OR⁸, —(C₁-C₃ alkylene)SR⁸, —(C₁-C₃ alkylene)NR⁹R¹⁰, —(C₁-C₃alkylene)CF₃, —(C₁-C₃ alkylene)NO₂, —C═NH(OR⁸), —(C₁-C₃ alkylene)C(O)R⁸,—(C₁-C₃ alkylene)OC(O)R⁸, —(C₁-C₃ alkylene)C(O)OR⁸, —(C₁-C₃alkylene)C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)OC(O)NR⁹R¹⁰, —(C₁-C₃alkylene)NR⁸C(O)R⁹, —(C₁-C₃ alkylene)NR⁸C(O)OR⁹, —(C₁-C₃alkylene)NR⁸C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)S(O)R⁸, —(C₁-C₃alkylene)S(O)₂R⁸, —(C₁-C₃ alkylene)NR⁸S(O)R⁹, —C(O)(C₁-C₃alkylene)NR⁸S(O)R⁹, —(C₁-C₃ alkylene)NR⁸S(O)₂R⁹, —(C₁-C₃alkylene)C(O)NR⁸S(O)₂R⁹, —(C₁-C₃ alkylene)S(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)₂NR⁹R¹⁰, —(C₁-C₃ alkylene)P(O)(OR⁹)(OR¹⁰), —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-12-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-10-membered heteroaryl) or -(C₁-C₃alkylene)(C₆-C₁₄ aryl), wherein each R⁶ and R⁷ is independentlyoptionally substituted by halogen, oxo, —OR¹¹, —NR¹¹R¹², —C(O)R¹¹, —CN,—S(O)R¹¹, —S(O)₂R¹¹, —P(O)(OR¹¹)(OR¹²), —(C₁-C₃ alkylene)OR¹¹, —(C₁-C₃alkylene)NR¹¹R¹², —(C₁-C₃ alkylene)C(O)R¹¹, —(C₁-C₃ alkylene)S(O)R¹¹,—(C₁-C₃ alkylene)S(O)₂R¹¹, —(C₁-C₃ alkylene)P(O)(OR¹¹)(OR¹²), C₃-C₈cycloalkyl, or C₁-C₆ alkyl optionally substituted by oxo, —OH orhalogen; R⁸ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5-6-membered heteroaryl,3-6-membered heterocyclyl, —(C₁-C₃ alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃alkylene)(C₆-C₁₄ aryl), —(C₁-C₃ alkylene)(5-6-membered heteroaryl), or-(C₁-C₃ alkylene)(3-6-membered heterocyclyl), wherein the C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl,5-6-membered heteroaryl, 3-6-membered heterocyclyl, —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(C₆-C₁₄ aryl), —(C₁-C₃alkylene)(5-6-membered heteroaryl), and -(C₁-C₃ alkylene)(3-6-memberedheterocyclyl) are independently optionally substituted by halogen, oxo,—CN, —OR¹³, —NR¹³R¹⁴, —P(O)(OR¹³)(OR¹⁴), phenyl optionally substitutedby halogen, or C₁-C₆ alkyl optionally substituted by halogen, —OH oroxo; R⁹ and R¹⁰ are each independently hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5-6-memberedheteroaryl, 3-6 membered heterocyclyl, —(C₁-C₃ alkylene)NR¹¹R¹², C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-6-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-6-membered heteroaryl) or -(C₁-C₃alkylene)(C₆ aryl), wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5-6-membered heteroaryl, 3-6membered heterocyclyl, —(C₁-C₃ alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃alkylene)(3-6-membered heterocyclyl), —(C₁-C₃ alkylene)(5-6-memberedheteroaryl) and —(C₁-C₃ alkylene)(C₆ aryl) are independently optionallysubstituted by halogen, oxo, —CN, —OR¹³, —NR¹³R¹⁴ or C₁-C₆ alkyloptionally substituted by halogen, —OH or oxo; or R⁹ and R¹⁰ are takentogether with the atom to which they attached to form a 3-6 memberedheterocyclyl optionally substituted by halogen, oxo, —OR¹³, —NR³R¹⁴ orC₁-C₆ alkyl optionally substituted by halogen, oxo or —OH; R¹¹ and R¹²are each independently hydrogen, C₁-C₆ alkyl optionally substituted byhalogen or oxo, C₂-C₆ alkenyl optionally substituted by halogen or oxo,or C₂-C₆ alkynyl optionally substituted by halogen or oxo; or R¹¹ andR¹² are taken together with the atom to which they attached to form a3-6 membered heterocyclyl optionally substituted by halogen, oxo orC₁-C₆ alkyl optionally substituted by halogen or oxo; and R¹³ and R¹⁴are each independently hydrogen, C₁-C₆ alkyl optionally substituted byhalogen or oxo, C₂-C₆ alkenyl optionally substituted by halogen or oxo,or C₂-C₆ alkynyl optionally substituted by halogen or oxo; or R¹³ andR¹⁴ are taken together with the atom to which they attached to form a3-6 membered heterocyclyl optionally substituted by halogen, oxo orC₁-C₆ alkyl optionally substituted by oxo or halogen.
 2. The compound ofclaim 1, or a tautomer or isomer thereof, or a pharmaceuticallyacceptable salt of any of the foregoing, wherein: R¹ is H or C₁-C₆ alkylwherein the C₁-C₆ alkyl of R¹ is optionally substituted with oxo orR^(a); R² is H, R^(b) or oxo; R⁴ is H, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, halogen, —CN, —OR⁸, —SR⁸, —NO₂, —C═NH(OR⁸), —C(O)R⁸,—OC(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁸C(O)OR⁹,—NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, —NR⁸S(O)R⁹, —C(O)NR⁸S(O)R⁹,—NR⁸S(O)₂R⁹, —C(O)NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰,—P(O)(OR⁹)(OR¹⁰), C₃-C₆ cycloalkyl, 3-12-membered heterocyclyl, 5- to10-membered heteroaryl, C₆-C₁₄ aryl, —(C₁-C₃ alkylene)CN, —(C₁-C₃alkylene)OR⁸, —(C₁-C₃ alkylene)SR⁸, —(C₁-C₃ alkylene)NR⁹R¹⁰, —(C₁-C₃alkylene)CF₃, —(C₁-C₃ alkylene)NO₂, —C═NH(OR⁸), —(C₁-C₃ alkylene)C(O)R⁸,—(C₁-C₃ alkylene)OC(O)R⁸, —(C₁-C₃ alkylene)C(O)OR⁸, —(C₁-C₃alkylene)C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)OC(O)NR⁹R¹⁰, —(C₁-C₃alkylene)NR⁸C(O)R⁹, —(C₁-C₃ alkylene)NR⁸C(O)OR⁹, —(C₁-C₃alkylene)NR⁸C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)S(O)R⁸, —(C₁-C₃alkylene)S(O)₂R⁸, —(C₁-C₃ alkylene)NR⁸S(O)R⁹, —C(O)(C₁-C₃alkylene)NR⁸S(O)R⁹, —(C₁-C₃ alkylene)NR⁸S(O)₂R⁹, —(C₁-C₃alkylene)C(O)NR⁸S(O)₂R⁹, —(C₁-C₃ alkylene)S(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)₂NR⁹R¹⁰, —(C₁-C₃ alkylene)P(O)(OR⁹)(OR¹⁰), —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-12-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-10-membered heteroaryl) or -(C₁-C₃alkylene)(C₆-C₁₄ aryl), each of which is independently optionallysubstituted by halogen, oxo, —OR¹¹, —NR¹¹R¹², —C(O)R¹¹, —CN, —S(O)R¹¹,—S(O)₂R¹¹, —P(O)(OR¹¹)(OR¹²), —(C₁-C₃ alkylene)OR¹¹, —(C₁-C₃alkylene)NR¹¹R¹², —(C₁-C₃ alkylene)C(O)R¹¹, —(C₁-C₃ alkylene)S(O)R¹¹,—(C₁-C₃ alkylene)S(O)₂R¹¹, —(C₁-C₃ alkylene)P(O)(OR¹¹)(OR¹²), C₃-C₈cycloalkyl, or C₁-C₆ alkyl optionally substituted by oxo, —OH orhalogen; R³ and R⁵ are each independently H or R^(c); each R^(a), R^(b),and R^(c) is independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,halogen, —CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C═NH(OR⁸), —C(O)R⁸, —OC(O)R⁸,—C(O)OR⁸, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)OR⁹,—NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, —NR⁸S(O)R⁹, —C(O)NR⁸S(O)R⁹,—NR⁸S(O)₂R⁹, —C(O)NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰,—P(O)(OR⁹)(OR¹⁰), C₃-C₆ cycloalkyl, 3-12-membered heterocyclyl, 5- to10-membered heteroaryl, C₆-C₁₄ aryl, —(C₁-C₃ alkylene)CN, —(C₁-C₃alkylene)OR⁸, —(C₁-C₃ alkylene)SR⁸, —(C₁-C₃ alkylene)NR⁹R¹⁰, —(C₁-C₃alkylene)CF₃, —(C₁-C₃ alkylene)NO₂, —C═NH(OR⁸), —(C₁-C₃ alkylene)C(O)R⁸,—(C₁-C₃ alkylene)OC(O)R⁸, —(C₁-C₃ alkylene)C(O)OR⁸, —(C₁-C₃alkylene)C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)OC(O)NR⁹R¹⁰, —(C₁-C₃alkylene)NR⁸C(O)R⁹, —(C₁-C₃ alkylene)NR⁸C(O)OR⁹, —(C₁-C₃alkylene)NR⁸C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)S(O)R⁸, —(C₁-C₃alkylene)S(O)₂R⁸, —(C₁-C₃ alkylene)NR⁸S(O)R⁹, —C(O)(C₁-C₃alkylene)NR⁸S(O)R⁹, —(C₁-C₃ alkylene)NR⁸S(O)₂R⁹, —(C₁-C₃alkylene)C(O)NR⁸S(O)₂R⁹, —(C₁-C₃ alkylene)S(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)₂NR⁹R¹⁰, —(C₁-C₃ alkylene)P(O)(OR⁹)(OR¹⁰), —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-12-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-10-membered heteroaryl) or -(C₁-C₃alkylene)(C₆-C₁₄ aryl), wherein each R^(a), R^(b), and R^(c) isindependently optionally substituted by halogen, oxo, —OR¹¹, —NR¹¹R¹²,—C(O)R¹¹, —CN, —S(O)R¹¹, —S(O)₂R¹¹, —P(O)(OR¹¹)(OR¹²), —(C₁-C₃alkylene)OR¹¹, —(C₁-C₃ alkylene)NR¹¹R¹², —(C₁-C₃ alkylene)C(O)R¹¹,—(C₁-C₃ alkylene)S(O)R¹¹, —(C₁-C₃ alkylene)S(O)₂R¹¹, —(C₁-C₃alkylene)P(O)(OR¹¹)(OR¹²), C₃-C₈ cycloalkyl, or C₁-C₆ alkyl optionallysubstituted by oxo, —OH or halogen; wherein when R¹ is C₁-C₆ alkyl, R⁴is other than —NR⁹R¹⁰ and R³ is other than —OC(O)R⁸; ------ is a singlebond or a double bond, wherein when ------- is a double bond, R² is oxo;

is a single bond or a double bond, wherein when

is a double bond, R⁴ is oxo; one of ------ and

is a double bond and the other is a single bond; A is C₆-C₁₂ aryl, 5- to10-membered heteroaryl, 9- to 10-membered carbocycle, or 9- to10-membered heterocycle, wherein the C₆-C₁₂ aryl, 5- to 10-memberedheteroaryl or 9- to 10-membered carbocycle, or 9- to 10-memberedheterocycle of A is optionally further substituted with R⁶; B is phenyl,5- to 6-membered heteroaryl, 5- to 6-membered carbocycle, 5- to6-membered heterocycle, or 9- to 10-membered heteroaryl, wherein thephenyl, 5- to 6-membered heteroaryl, 5- to 6-membered carbocycle, 5- to6-membered heterocycle, or 9- to 10-membered heteroaryl of B isoptionally further substituted with R⁷; wherein when B is 5- to6-membered heterocycle, A is other than phenyl optionally furthersubstituted with R⁶ or pyridyl optionally further substituted with R⁶;each R⁶ and R⁷ is independently oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, halogen, —CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C═NH(OR⁸), —C(O)R⁸,—OC(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)OR⁹,—NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, —NR⁸S(O)R⁹, —C(O)NR⁸S(O)R⁹,—NR⁸S(O)₂R⁹, —C(O)NR⁸S(O)₂R⁹, —S(O)NR⁹R¹⁰, —S(O)₂NR⁹R¹⁰,—P(O)(OR⁹)(OR¹⁰), C₃-C₆ cycloalkyl, 3-12-membered heterocyclyl, 5- to10-membered heteroaryl, C₆-C₁₄ aryl, —(C₁-C₃ alkylene)CN, —(C₁-C₃alkylene)OR⁸, —(C₁-C₃ alkylene)SR⁸, —(C₁-C₃ alkylene)NR⁹R¹⁰, —(C₁-C₃alkylene)CF₃, —(C₁-C₃ alkylene)NO₂, —C═NH(OR⁸), —(C₁-C₃ alkylene)C(O)R⁸,—(C₁-C₃ alkylene)OC(O)R⁸, —(C₁-C₃ alkylene)C(O)OR⁸, —(C₁-C₃alkylene)C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)OC(O)NR⁹R¹⁰, —(C₁-C₃alkylene)NR⁸C(O)R⁹, —(C₁-C₃ alkylene)NR⁸C(O)OR⁹, —(C₁-C₃alkylene)NR⁸C(O)NR⁹R¹⁰, —(C₁-C₃ alkylene)S(O)R⁸, —(C₁-C₃alkylene)S(O)₂R⁸, —(C₁-C₃ alkylene)NR⁸S(O)R⁹, —C(O)(C₁-C₃alkylene)NR⁸S(O)R⁹, —(C₁-C₃ alkylene)NR⁸S(O)₂R⁹, —(C₁-C₃alkylene)C(O)NR⁸S(O)₂R⁹, —(C₁-C₃ alkylene)S(O)NR⁹R¹⁰, —(C₁-C₃alkylene)S(O)₂NR⁹R¹⁰, —(C₁-C₃ alkylene)P(O)(OR⁹)(OR¹⁰), —(C₁-C₃alkylene)(C₃-C₆ cycloalkyl), —(C₁-C₃ alkylene)(3-12-memberedheterocyclyl), —(C₁-C₃ alkylene)(5-10-membered heteroaryl) or -(C₁-C₃alkylene)(C₆-C₁₄ aryl), wherein each R⁶ and R⁷ is independentlyoptionally substituted by halogen, oxo, —OR¹¹, —NR¹¹R¹², —C(O)R¹¹, —CN,—S(O)R¹¹, —S(O)₂R¹¹, —P(O)(OR¹¹)(OR¹²), —(C₁-C₃ alkylene)OR¹¹, —(C₁-C₃alkylene)NR¹¹R¹², —(C₁-C₃ alkylene)C(O)R¹¹, —(C₁-C₃ alkylene)S(O)R¹¹,—(C₁-C₃ alkylene)S(O)₂R¹¹, —(C₁-C₃ alkylene)P(O)(OR¹¹)(OR¹²), C₃-C₈cycloalkyl, or C₁-C₆ alkyl optionally substituted by oxo, —OH orhalogen; R⁸ is independently hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5-6-membered heteroaryl or3-6-membered heterocyclyl, wherein the C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl, 5-6-membered heteroaryl and3-6-membered heterocyclyl are independently optionally substituted byhalogen, oxo, —CN, —OR¹³, —NR¹³R¹⁴, —P(O)(OR¹³)(OR¹⁴), phenyl optionallysubstituted by halogen, or C₁-C₆ alkyl optionally substituted byhalogen, —OH or oxo; R⁹ and R¹⁰ are each independently hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl,5-6-membered heteroaryl or 3-6 membered heterocyclyl, wherein the C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₆ cycloalkyl, C₆-C₁₄ aryl,5-6-membered heteroaryl and 3-6 membered heterocyclyl are independentlyoptionally substituted by halogen, oxo, —CN, —OR¹³, —NR¹³R¹⁴ or C₁-C₆alkyl optionally substituted by halogen, —OH or oxo; or R⁹ and R¹⁰ aretaken together with the atom to which they attached to form a 3-6membered heterocyclyl optionally substituted by halogen, oxo, —OR¹³,—NR³R¹⁴ or C₁-C₆ alkyl optionally substituted by halogen, oxo or —OH;R¹¹ and R¹² are each independently hydrogen, C₁-C₆ alkyl optionallysubstituted by halogen or oxo, C₂-C₆ alkenyl optionally substituted byhalogen or oxo, or C₂-C₆ alkynyl optionally substituted by halogen oroxo; or R¹¹ and R¹² are taken together with the atom to which theyattached to form a 3-6 membered heterocyclyl optionally substituted byhalogen, oxo or C₁-C₆ alkyl optionally substituted by halogen or oxo;and R¹³ and R¹⁴ are each independently hydrogen, C₁-C₆ alkyl optionallysubstituted by halogen or oxo, C₂-C₆ alkenyl optionally substituted byhalogen or oxo, or C₂-C₆ alkynyl optionally substituted by halogen oroxo; or R¹³ and R¹⁴ are taken together with the atom to which theyattached to form a 3-6 membered heterocyclyl optionally substituted byhalogen, oxo or C₁-C₆ alkyl optionally substituted by oxo or halogen. 3.The compound of claim 1, or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, wherein R¹ isH or methyl.
 4. The compound of claim 1, or a tautomer or isomerthereof, or a pharmaceutically acceptable salt of any of the foregoing,wherein R⁵ is H, C₁-C₆ alkyl, halogen, —CN, or —OR⁸.
 5. The compound ofclaim 1, wherein the compound is of the Formula (II):

or a tautomer or isomer thereof, or a pharmaceutically acceptable saltof any of the foregoing, wherein A, B, R¹, R³, R⁴, and R⁵ are as definedfor Formula (I).
 6. The compound of claim 5, or a tautomer or isomerthereof, or a pharmaceutically acceptable salt of any of the foregoing,wherein at least one of R³, R⁴, and R⁵ is not H.
 7. The compound ofclaim 5, or a tautomer or isomer thereof, or a pharmaceuticallyacceptable salt of any of the foregoing, wherein at least one of R³, R⁴,and R⁵ is C₁-C₆ alkyl, halogen, C₆-C₁₄ aryl, —CN, or —OR⁸.
 8. Thecompound of claim 5, or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, wherein R¹,R³, R⁴, and R⁵ are each H.
 9. The compound of claim 1, wherein thecompound is of the Formula (III):

or a tautomer or isomer thereof, or a pharmaceutically acceptable saltof any of the foregoing, wherein A, B, R¹, R², R³, and R⁵ are as definedfor Formula (I).
 10. The compound of claim 1, or a tautomer or isomerthereof, or a pharmaceutically acceptable salt of any of the foregoing,wherein at least one of R², R³, and R⁵ is not H.
 11. The compound ofclaim 9, or a tautomer or isomer thereof, or a pharmaceuticallyacceptable salt of any of the foregoing, wherein at least one of R², R³,and R⁵ is C₁-C₆ alkyl, halogen, C₆-C₁₄ aryl, —CN, or —OR⁸.
 12. Thecompound of claim 9, or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, wherein R¹,R², R³, and R⁵ are each H.
 13. The compound of claim 1, or a tautomer orisomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, wherein R¹ is H.
 14. The compound of claim 1, or a tautomeror isomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, wherein A is C₆-C₁₂ aryl optionally further substituted withR⁶.
 15. The compound of claim 14, or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, wherein A isphenyl or naphthyl, optionally substituted with R⁶.
 16. The compound ofclaim 1, or a tautomer or isomer thereof, or a pharmaceuticallyacceptable salt of any of the foregoing, wherein A is 5- to 10-memberedheteroaryl optionally further substituted with R⁶.
 17. The compound ofclaim 1, or a tautomer or isomer thereof, or a pharmaceuticallyacceptable salt of any of the foregoing, wherein A is

wherein R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), and R^(6f) are eachindependently H, C₁-C₆ alkyl, halogen, —CN, or —OC₁-C₆ alkyl.
 18. Thecompound of claim 1, or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, wherein A is

wherein R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), and R^(6g) are eachindependently H, C₁-C₆ alkyl, halogen, —CN, or —OC₁-C₆ alkyl.
 19. Thecompound of claim 1, or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, wherein A is

wherein X¹ is selected from the group consisting of N, C, and CH; X² isselected from the group consisting of NH, O, and S; and R^(6a), R^(6b),and R^(6c) are each independently H, C₁-C₆ alkyl, halogen, —CN, or—OC₁-C₆ alkyl.
 20. The compound of claim 1, or a tautomer or isomerthereof, or a pharmaceutically acceptable salt of any of the foregoing,wherein A is

wherein X¹ is selected from the group consisting of N, C, and CH; X² isselected from the group consisting of NH, O, and S; and R^(6g), R^(6b),and R^(6c) are each independently H, C₁-C₆ alkyl, halogen, —CN, or—OC₁-C₆ alkyl.
 21. The compound of claim 16, or a tautomer or isomerthereof, or a pharmaceutically acceptable salt of any of the foregoing,wherein A is selected from the group consisting of pyridyl, quinolinyl,isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, naphthyridinyl,benzoxazolyl, benzothiazolyl, benzoimidazoyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl,oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl,isoindolyl, indazolyl, benzotriazolyl, benzofuranyl, benzoisoxazolyl,benzoxadiazolyl, benzothiophenyl, benzoisothiazolyl, benzothiadiazolyl,pyrrolopyridinyl, pyrazolopyridinyl, imidazopyridinyl,triazolopyridinyl, furopyridinyl, oxazolopyridinyl, isoxazolopyridinyl,oxadiazolopyridinyl, thienopyridinyl, thiazolopyridinyl,isothiazolopyridinyl, thiadiazolopyridinyl, thienopyridinyl,phthalazinyl, pyrazolothiazolyl, pyrazolothiazolyl and imidazothiazolyl,each optionally substituted with R⁶.
 22. The compound of claim 16, or atautomer or isomer thereof, or a pharmaceutically acceptable salt of anyof the foregoing, wherein A is selected from the group consisting of:

each optionally substituted with R⁶.
 23. The compound of claim 1, or atautomer or isomer thereof, or a pharmaceutically acceptable salt of anyof the foregoing, wherein A is a 9- to 10-membered carbocycle optionallyfurther substituted with R⁶.
 24. The compound of claim 23, or a tautomeror isomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, wherein A is selected from the group consisting ofdecahydronaphthalenyl, octahydroindenyl, 1,2,3,4-tetrahydronaphthalenyl,and 2,3-dihydroindenyl, each optionally substituted with R⁶.
 25. Thecompound of claim 1, or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, wherein A is a9- to 10-membered heterocycle optionally further substituted with R⁶.26. The compound of claim 24, or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, wherein A isselected from the group consisting of tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl,indolinyl, isoindolinyl, tetrahydronaphthyridinyl andhexahydrobenzoimidazolyl, each optionally further substituted with R⁶.27. The compound of claim 1, or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, wherein A isselected from the group consisting of

each optionally substituted with R⁶.
 28. The compound of claim 14, or atautomer or isomer thereof, or a pharmaceutically acceptable salt of anyof the foregoing, wherein each R⁶ is independently selected from thegroup consisting of halogen, —CN, —OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C(O)R⁸,—C(O)OR⁸, —C(O)NR⁹R¹⁰, —C(O)NR⁸S(O)₂R⁹, —OC(O)R⁸, —OC(O)NR⁹R¹⁰,—NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰, —S(O)R⁸, —S(O)₂R⁸, C₃-C₆ cycloalkyl andC₁-C₆ alkyl optionally substituted by halogen.
 29. The compound of claim28, or a tautomer or isomer thereof, or a pharmaceutically acceptablesalt of any of the foregoing, wherein each R⁶ is independently selectedfrom the group consisting of C₁-C₆ alkyl, halogen, —CN, and —OR⁸. 30.The compound of claim 1, or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, wherein A isselected from the group consisting of:


31. The compound of claim 1, or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, wherein B isphenyl, optionally further substituted with R⁷.
 32. The compound ofclaim 1, or a tautomer or isomer thereof, or a pharmaceuticallyacceptable salt of any of the foregoing, wherein B is 5- to 6-memberedheteroaryl optionally further substituted with R⁷.
 33. The compound ofclaim 32, or a tautomer or isomer thereof, or a pharmaceuticallyacceptable salt of any of the foregoing, wherein B is pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl,oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,or tetrazinyl, each optionally substituted with R⁷.
 34. The compound ofclaim 32, or a tautomer or isomer thereof, or a pharmaceuticallyacceptable salt of any of the foregoing, wherein B is furanyl,pyridinyl, oxazoyl, or oxadiazoyl, each optionally substituted with R⁷.35. The compound of claim 1, or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, wherein B is a5- to 6-membered fully saturated carbocycle optionally furthersubstituted with R⁷.
 36. The compound of claim 35, or a tautomer orisomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, wherein B is cyclopentyl or cyclohexyl, optionally furthersubstituted with R⁷.
 37. The compound of claim 1, or a tautomer orisomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, wherein B is a 5- to 6-membered fully saturated heterocycleoptionally further substituted with R⁷.
 38. The compound of claim 37, ora tautomer thereof or isomer thereof, or a pharmaceutically acceptablesalt of any of the foregoing, wherein B is pyrrolidinyl, pyrazolidinyl,imidazolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, tetrahydrothiophenyl,oxathiolanyl, sulfolanyl, piperidinyl, piperazinyl, tetrahydropyranyl,dioxanyl, thianyl, dithianyl, trithianyl, morpholinyl, thiomorpholinyloptionally further substituted with R⁷.
 39. The compound of claim 1, ora tautomer or isomer thereof, or a pharmaceutically acceptable salt ofany of the foregoing, wherein B is a 9- to 10-membered heteroaryloptionally further substituted with R⁷.
 40. The compound of claim 39, ora tautomer or isomer thereof, or a pharmaceutically acceptable salt ofany of the foregoing, wherein B is selected from the group consisting ofpyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl,quinazolinyl, naphthyridinyl, benzoxazolyl, benzothiazolyl,benzoimidazoyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl,thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzofuranyl, benzoisoxazolyl, benzoxadiazolyl, benzothiophenyl,benzoisothiazolyl, benzothiadiazolyl, pyrrolopyridinyl,pyrazolopyridinyl, imidazopyridinyl, triazolopyridinyl, furopyridinyl,oxazolopyridinyl, isoxazolopyridinyl, oxadiazolopyridinyl,thienopyridinyl, thiazolopyridinyl, isothiazolopyridinyl,thiadiazolopyridinyl, thienopyridinyl, phthalazinyl, pyrazolothiazolyl,pyrazolothiazolyl and imidazothiazolyl, each optionally substituted withR⁷.
 41. The compound of claim 1, or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, wherein eachR⁷ is independently selected from the group consisting of halogen, —CN,—OR⁸, —SR⁸, —NR⁹R¹⁰, —NO₂, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁹R¹⁰,—C(O)NR⁸S(O)₂R⁹, —OC(O)R⁸, —OC(O)NR⁹R¹⁰, —NR⁸C(O)R⁹, —NR⁸C(O)NR⁹R¹⁰,—S(O)R⁸, —S(O)₂R⁸, C₃-C₆ cycloalkyl and C₁-C₆ alkyl optionallysubstituted by halogen.
 42. The compound of claim 41, or a tautomer orisomer thereof, or a pharmaceutically acceptable salt of any of theforegoing, wherein R⁷ is halogen.
 43. The compound of claim 1, or atautomer or isomer thereof, or a pharmaceutically acceptable salt of anyof the foregoing, wherein B is selected from the group consisting of:


44. A compound selected from the group consisting of

or a tautomer or isomer thereof, or a pharmaceutically acceptable saltof any of the foregoing.
 45. The compound of claim 44, wherein thecompound is selected from in the group consisting of

or a tautomer or isomer thereof, or a pharmaceutically acceptable saltof any of the foregoing.
 46. The compound of claim 44, or apharmaceutically acceptable salt thereof.
 47. A pharmaceuticalcomposition comprising a compound of claim 1, or a tautomer or isomerthereof, or a pharmaceutically acceptable salt of any of the foregoing,and a pharmaceutically acceptable carrier.
 48. A method of treatingcancer in an individual in need thereof comprising administering to theindividual a therapeutically effective amount of a compound of claim 1,or a tautomer or isomer thereof, or a pharmaceutically acceptable saltof any of the foregoing.
 49. A method of inhibiting adenosine receptorsof subtypes A_(2a), A_(2b) or A₃ in a cell, comprising administering acompound of claim 1, or a tautomer or isomer thereof, or apharmaceutically acceptable salt of any of the foregoing, to the cells.50. The method of claim 49, wherein the adenosine receptors are ofsubtype A_(2a).
 51. A kit comprising a compound of claim 1, or atautomer or isomer thereof, or a pharmaceutically acceptable salt of anyof the foregoing.
 52. The compound of claim 44, wherein the compound isselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 53. The compound of claim44, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 54. The compound of claim44, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 55. The compound of claim44, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 56. The compound of claim44, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 57. The compound of claim44, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 58. The compound of claim44, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 59. The compound of claim44, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 60. The compound of claim44, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 61. The compound of claim44, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 62. The compound of claim44, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 63. The compound of claim44, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 64. The compound of claim44, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 65. The compound of claim44, or a pharmaceutically acceptable salt thereof, wherein the compoundis

or a pharmaceutically acceptable salt thereof.
 66. The compound of claim44, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 67. The compound of claim44, wherein the compound is


68. The compound of claim 44, wherein the compound is


69. The compound of claim 44, wherein the compound is


70. The compound of claim 44, wherein the compound is


71. The compound of claim 44, wherein the compound is


72. The compound of claim 44, wherein the compound is


73. The compound of claim 44, wherein the compound is


74. The compound of claim 44, wherein the compound is


75. The compound of claim 44, or a pharmaceutically acceptable saltthereof, wherein the compound is


76. The compound of claim 44, wherein the compound is